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Yang, Zhiyong, Ning Zhao, Jing Cui, Heshui Wu, Jiongxin Xiong y Tao Peng. "Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210". Cellular Oncology 43, n.º 1 (12 de noviembre de 2019): 123–36. http://dx.doi.org/10.1007/s13402-019-00476-6.
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Abstract Purpose Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance. Methods GEM-sensitive BxPC-3-derived BxS and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived BxR cells (BxR-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in BxS and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo. Results BxR-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in BxS and PANC-1 cells. Elevated miR-210 expression levels were detected in BxR-CSCs and BxR-CSC-derived exosomes compared to those in BxS-CSCs and BxS-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in BxS and PANC-1 cells cultured with BxR-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in BxS cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by BxR-CSC-derived exosomes. Conclusions Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.
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Walter, Karolin, Eva Rodriguez-Aznar, Monica S. Ventura Ferreira, Pierre-Olivier Frappart, Tabea Dittrich, Kanishka Tiwary, Sabine Meessen et al. "Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells". Cancers 13, n.º 13 (23 de junio de 2021): 3145. http://dx.doi.org/10.3390/cancers13133145.
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To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.
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Malaer, Joseph D. y Porunelloor A. Mathew. "Cancer stem cells inhibit NK cell effector function via PCNA-NKp44 interaction". Journal of Immunology 202, n.º 1_Supplement (1 de mayo de 2019): 134.12. http://dx.doi.org/10.4049/jimmunol.202.supp.134.12.
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Abstract NK cells participate in the innate immune response against infection and cancer without prior sensitization. NK cell function depends on a balance of signals transmitted from activating and inhibitory receptors interacting with ligands on the surface of cells. Cancer cells may evade NK-mediated killing by expressing ligands for inhibitory receptors. Proliferating cell nuclear antigen (PCNA) associates with MHC I and forms the inhibitory ligand for NKp44, resulting in the inhibition of NK function. Cancer stem cells (CSC), a unique subset of tumor cells, possess a stem-cell-like phenotype and are thought to facilitate metastasis by escaping NK cell effector function. Pancreatic and colon CSC can be identified by co-expression of surface markers CD44 and CD133. In both cell lines, Panc-1 and HCT 116, cell surface PCNA is associated with co-expression of CD44 and CD133 as well as increased CSC transcription factor expression (NANOG, SOX2, and Oct-4). Blocking the interaction of NKp44 and PCNA enhanced the specific lysis of cells by NK cells. Collectively these data demonstrate that surface PCNA, CD44, and CD133 co-expression is a marker of pancreatic and colon CSC. Our research implicates that blocking NKp44-PCNA interaction may provide a novel immunotherapeutic target for pancreatic and colon cancer stem cells and prevent metastasis.
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Smith, Ebony y Tuan Tran. "Recurrence of Pancreatic Cancer Presenting as Choroidal Metastasis: A Case Report". Case Reports in Ophthalmology 12, n.º 3 (25 de octubre de 2021): 854–58. http://dx.doi.org/10.1159/000519689.
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A patient initially diagnosed as having central serous chorioretinopathy (CSC) presented to a clinic with recurrence of pancreatic cancer manifesting as choroidal metastasis. He was initially diagnosed with CSC by a local ophthalmologist 8 weeks earlier and subsequently presented to our clinic for second opinion after further loss of vision. His medical history was significant for locally advanced pancreatic cancer that was resected by pancreaticoduodenectomy and was treated with adjuvant Folfirinox chemotherapy that was completed 12 months earlier. On examination, there was a large serous retinal detachment overlying a large pale ill-defined elevated choroidal lesion. A diagnosis of choroidal metastasis from recurrence of his pancreatic cancer was made. The diagnosis of choroidal metastasis of his pancreatic cancer represented recurrence of his pancreatic cancer that is associated with high mortality. Early recognition by clinical assessment may allow timely management with chemotherapy and radiation, and potentially prolong survival.
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Chen, Yu-Jen, Yu-Chuen Huang, Tung-Hu Tsai y Hui-Fen Liao. "Effect of Wasabi Component 6-(Methylsulfinyl)hexyl Isothiocyanate and Derivatives on Human Pancreatic Cancer Cells". Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/494739.
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The naturally occurring compound 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) was isolated fromWasabia japonica(Wasabi), a pungent spice used in Japanese food worldwide. The synthetic derivatives 6-(methylsulfenyl)hexyl isothiocyanate (I7447) and 6-(methylsulfonyl)hexyl isothiocyanate (I7557) are small molecule compounds derived from 6-MITC. This study aimed to evaluate the effect of these compounds on human pancreatic cancer cells. Human pancreatic cancer cell lines PANC-1 and BxPC-3 were used to perform an MTT assay for cell viability and Liu’s stain for morphological observation. The cell cycle was analyzed by DNA histogram. Aldehyde dehydrogenase (ALDH) activity was used as a marker for cancer stem cells (CSC). Western blotting was performed for the expression of proteins related to CSC signaling. The results showed that compounds 6-MITC and I7557, but not I7447, inhibited viability of both PANC-1 and BxPC-3 cells. Morphological observation showed mitotic arrest and apoptosis in 6-MITC- and I7557-treated cells. These two compounds induced G2/M phase arrest and hypoploid population. Percentages of ALDH-positive PANC-1 cells were markedly reduced by 6-MITC and I7557 treatment. The expression of CSC signaling molecule SOX2, but not NOTCH1, ABCG2, Sonic hedgehog, or OCT4, was inhibited by 6-MITC and I7557. In conclusion, wasabi compounds 6-MITC and I7557 may possess activity against the growth and CSC phenotypes of human pancreatic cancer cells.
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Malaer, Joseph D. y Porunelloor A. Mathew. "Pancreatic and colon cancer stem cells escape NK cell effector function via PCNA–NKp44 interaction". Journal of Immunology 204, n.º 1_Supplement (1 de mayo de 2020): 88.16. http://dx.doi.org/10.4049/jimmunol.204.supp.88.16.
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Abstract Natural killer (NK) cells play an important role in the innate immune response against cancer. Unlike B or T lymphocytes, NK cells do not require prior sensitization and can immediately respond to target cells. NK cell function depends on a balance of signals transmitted from activating and inhibitory receptors interacting with ligands on the surface of cells. Cancer cells may escape NK-mediated responses by expressing inhibitory ligands. Proliferating cell nuclear antigen (PCNA), in association MHC I, forms the inhibitory ligand for NKp44. Cancer stem cells (CSC), a unique subset of tumor cells, possess a stem-cell-like phenotype and are thought to facilitate metastasis by escaping NK cell effector function. CSC can be identified by a variety of markers such as surface co-expression of CD44 and CD133. In both Panc-1 and HCT 116 cell lines, surface PCNA is associated with co-expression of CD44 and CD133. Triple positive (PCNA+CD44+CD133+) cells have increased CSC transcription factor (NANOG, SOX2, and Oct-4) expression compared to double positive (PCNA−CD44+CD133+) or negative cells. Additionally, blocking the PCNA–NKp44 interaction alters IFN-g secretion and increases specific lysis of cancer cells by NK cells. Taken together, these data suggest that surface co-expression of PCNA, CD44, and CD133 are markers of pancreatic and colon CSC and blocking the PCNA–NKp44 interaction may provide an immunotherapeutic approach to target pancreatic and colon CSC and prevent metastasis.
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Sasaki, Norihiko, Kazumi Hirano, Yuuki Shichi, Fujiya Gomi, Hisashi Yoshimura, Akira Matsushita, Masashi Toyoda y Toshiyuki Ishiwata. "Gp130-Mediated STAT3 Activation Contributes to the Aggressiveness of Pancreatic Cancer through H19 Long Non-Coding RNA Expression". Cancers 14, n.º 9 (19 de abril de 2022): 2055. http://dx.doi.org/10.3390/cancers14092055.
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Signaling pathways involving signal transducer and activator of transcription 3 (STAT3) play key roles in the aggressiveness of pancreatic ductal adenocarcinoma (PDAC), including their tumorigenesis, invasion, and metastasis. Cancer stem cells (CSCs) have been correlated with PDAC aggressiveness, and activation of STAT3 is involved in the regulation of CSC properties. Here, we investigated the involvement of interleukin-6 (IL-6) or the leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway and their role in pancreatic CSCs. In PDAC CSC-like cells formed by culturing on a low attachment plate, autocrine/paracrine IL-6 or LIF contributes to gp130/STAT3 pathway activation. Using a gp130 inhibitor, we determined that the gp130/STAT3 pathway contributes to the maintenance of stemness features, the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and the invasion of PDAC CSC-like cells. The gp130/STAT3 pathway also modulates the transforming growth factor (TGF)-β1/Smad pathway required for epithelial-mesenchymal transition induction through regulation of TGFβ-RII expression in PDAC CSC-like cells. Furthermore, chromatin immunoprecipitation assays revealed that p-STAT3 can access the active promoter region of H19 to influence this metastasis-related long non-coding RNA and contribute to its transcription in PDAC CSC-like cells. Therefore, the autocrine/paracrine IL-6 or LIF/gp130/STAT3 pathway in PDAC CSC-like cells may eventually facilitate invasion and metastasis, two hallmarks of malignancy. We propose that inhibition of the gp130/STAT3 pathway provides a promising strategy for targeting CSCs for the treatment of PDAC.
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Alcalá, Sonia, Paola Martinelli, Patrick C. Hermann, Christopher Heeschen y Bruno Sainz. "The Anthrax Toxin Receptor 1 (ANTXR1) Is Enriched in Pancreatic Cancer Stem Cells Derived from Primary Tumor Cultures". Stem Cells International 2019 (2 de mayo de 2019): 1–13. http://dx.doi.org/10.1155/2019/1378639.
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Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related mortality. Cancer stem cells (CSCs) have been shown to be the drivers of pancreatic tumor growth, metastasis, and chemoresistance, but our understanding of these cells is still limited by our inability to efficiently identify and isolate them. While a number of markers capable of identifying pancreatic CSCs (PaCSCs) have been discovered since 2007, there is no doubt that more markers are still needed. The anthrax toxin receptor 1 (ANTXR1) was identified as a functional biomarker of triple-negative breast CSCs, and PDAC patients stratified based on ANTXR1 expression levels showed increased mortality and enrichment of pathways known to be necessary for CSC biology, including TGF-β, NOTCH, Wnt/β-catenin, and IL-6/JAK/STAT3 signaling and epithelial to mesenchymal transition, suggesting that ANTXR1 may represent a putative PaCSC marker. In this study, we show that ANTXR1+ cells are not only detectable across a panel of 7 PDAC patient-derived xenograft primary cultures but ANTXR1 expression significantly increased in CSC-enriched 3D sphere cultures. Importantly, ANTXR1+ cells also coexpressed other known PaCSC markers such as CD44, CD133, and autofluorescence, and ANTXR1+ cells displayed enhanced CSC functional and molecular properties, including increased self-renewal and expression of pluripotency-associated genes, compared to ANTXR1- cells. Thus, this study validates ANTXR1 as a new PaCSC marker and we propose its use in identifying CSCs in this tumor type and its exploitation in the development of CSC-targeted therapies for PDAC.
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Cash, Timothy P., Sonia Alcalá, María del Rosario Rico-Ferreira, Elena Hernández-Encinas, Jennifer García, María Isabel Albarrán, Sandra Valle et al. "Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells". Cancers 12, n.º 7 (4 de julio de 2020): 1790. http://dx.doi.org/10.3390/cancers12071790.
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Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.
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Guo, Yichen, Yinan Jiang, J. Bart Rose, Ganji Purnachandra Nagaraju, Renata Jaskula-Sztul, Anita B. Hjelmeland, Adam W. Beck, Herbert Chen y Bin Ren. "Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity". Cells 11, n.º 23 (1 de diciembre de 2022): 3885. http://dx.doi.org/10.3390/cells11233885.
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Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.
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Molczyk, Caitlin, Elizabeth Thomas, Lubaba Zaman, Paran Goel y Rakesh K. Singh. "Abstract 894: CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 894. http://dx.doi.org/10.1158/1538-7445.am2022-894.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States. Often diagnosed late in disease progression, PDAC is notorious for chemotherapy resistance as well as having metastases. A cell population of interest aiding in this progression is the cancer stem cell (CSC). These cells are known for having high resistance to chemotherapy, along with propagating and re-building the tumor after most non-CSCs have been therapeutically targeted. Previous studies have determined CXCR4, ALDH1, CD24, CD44, and CD133 are markers of PDAC CSCs. In the present study, we investigated CXCR1 as a marker and therapeutic target for PDAC CSCs. CXCR1 is a G-coupled transmembrane protein receptor with downstream effects known to aid in anti-apoptosis, proliferation, and angiogenesis via binding CXCL8 and CXCL6. Already known to be a CSC marker and target in triple-negative breast cancer, initial studies by Chen et al. of CXCR1 in PDAC demonstrate CXCL8 induces increased tumorsphere formation in vitro, leading us to investigate CXCR1 in PDAC CSCs. Considering these findings, we hypothesized that PDAC cells with high CXCR1 activity exhibit increased CSC-like characteristics, and targeting CXCR1 will reduce those characteristics. To investigate the role of CXCR1 in PDAC CSC-like phenotype, we used two PDAC cell lines, CD18/HPAF and T3M4, and developed gemcitabine resistant (GemR) counterparts. These GemR cell lines were shown to have over 10-fold higher resistance than their respective parent cell lines. We treated with the CXCR1/2 antagonist navarixin at concentrations known to inhibit CXCR1. Using the parent cell lines’ relative IC50 concentrations for each drug, we treated cells for 72 hours. We used qRT-PCR and ELISAs for analysis of several known CSC markers and CXCR1 axis expression. From our results, we see the beginning trends of GemR cells having increased expression of CSC markers as well as gemcitabine-treated parent and resistant cells having increased expression. Using flow cytometry, we evaluated the CXCR1+ cell populations post-control and gemcitabine treatment. The population of CXCR1+ cells was higher in the gemcitabine-treated groups. Together, our observations suggest an association between CXCR1 and the CSC-like phenotype in PDAC. Citation Format: Caitlin Molczyk, Elizabeth Thomas, Lubaba Zaman, Paran Goel, Rakesh K. Singh. CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 894.
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Gluzman, Daniil, Aleksey Filchenkov y T. Ivanovskaya. "CELL SURFACE MOLECULAR MARKERS FOR IDENTIFICATION OF CANCER STEM CELL POPULATIONS (SYSTEMATIC REVIEW)". Problems in oncology 66, n.º 4 (1 de abril de 2020): 336–45. http://dx.doi.org/10.37469/0507-3758-2020-66-4-336-345.
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The present-day concepts of cancer stem cells (CSC) could be considered as the innovative breakthrough in understanding the nature of cancer that opens new vistas in clinical approach. The review summarizes the available data and the trends in the search of molecular markers that may be advantageous for CSC identification and isolation. The combinations of markers useful for studying CSC phenotype in glioblastoma, neuroblastoma, head and neck squamous cell carcinoma, melanoma, hepatocellular carcinoma, small-cell lung carcinoma, gastric cancer, colorectal cancer, pancreatic cancer, thyroid cancer, breast cancer, cervical cancer, ovarian cancer, renal cell carcinoma, prostate cancer, bladder cancer, and osteosarcoma are reviewed with the emphasis on the genes coding for marker molecules, their chromosomal localization as well as molecular weights of corresponding proteins. The data on the molecular and functional features of 35 CSC markers promising for CSC identification including 26 human CD antigens are briefly analyzed. Furthermore, two cytoplasmic proteins aldehyde dehydrogenase-1 and nestin that may be also recommended for CSC detection are characterized. The involvement of epithelial-to-mesenchymal transition in generation of CSC population is also assessed. The development of targeted therapies for CSC eradication that should be safe for normal stem cells of the corresponding organs and tissues is outlined.
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Gao, Yuran, Zhicheng Zhang, Kai Li, Liying Gong, Qingzhu Yang, Xuemei Huang, Chengcheng Hong, Mingfeng Ding y Huanjie Yang. "Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells". Cell Death & Disease 8, n.º 7 (julio de 2017): e2924-e2924. http://dx.doi.org/10.1038/cddis.2017.311.
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AbstractThe acquisition of epithelial–mesenchymal transition (EMT) and/or existence of a sub-population of cancer stem-like cells (CSC) are associated with malignant behavior and chemoresistance. To identify which factor could promote EMT and CSC formation and uncover the mechanistic role of such factor is important for novel and targeted therapies. In the present study, we found that the long intergenic non-coding RNA linc-DYNC2H1-4 was upregulated in pancreatic cancer cell line BxPC-3-Gem with acquired gemcitabine resistance. Knockdown of linc-DYNC2H1-4 decreased the invasive behavior of BxPC-3-Gem cells while ectopic expression of linc-DYNC2H1-4 promoted the acquisition of EMT and stemness of the parental sensitive cells. Linc-DYNC2H1-4 upregulated ZEB1, the EMT key player, which led to upregulation and downregulation of its targets vimentin and E-cadherin respectively, as well as enhanced the expressions of CSC makers Lin28, Nanog, Sox2 and Oct4. Linc-DYNC2H1-4 is mainly located in the cytosol. Mechanically, it could sponge miR-145 that targetsZEB1,Lin28,Nanog,Sox2,Oct4to restore these EMT and CSC-associated genes expressions. We proved thatMMP3, the nearby gene of linc-DYNC2H1-4 in the sense strand, was also a target of miR-145. Downregulation ofMMP3by miR-145 was reverted by linc-DYNC2H1-4, indicating that competing with miR-145 is one of the mechanisms for linc-DYNC2H1-4 to regulateMMP3. In summary, our results explore the important role of linc-DYNC2H1-4 in the acquisition of EMT and CSC, and the impact it has on gemcitabine resistance in pancreatic cancer cells.
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Asuthkar, Swapna, Victoria Stepanova, Tatiana Lebedeva, AiXuan L. Holterman, Norman Estes, Douglas B. Cines, Jasti S. Rao y Christopher S. Gondi. "Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer". Molecular Biology of the Cell 24, n.º 17 (septiembre de 2013): 2620–32. http://dx.doi.org/10.1091/mbc.e12-04-0306.
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Pancreatic ductal adenocarcinoma (PDAC) is almost always lethal. One of the underlying reasons for this lethality is believed to be the presence of cancer stem cells (CSC), which impart chemoresistance and promote recurrence, but the mechanisms responsible are unclear. Recently the poor prognosis of PDAC has been correlated with increased expression of urokinase plasminogen activator (uPA). In the present study we examine the role of uPA in the generation of PDAC CSC. We observe a subset of cells identifiable as a side population (SP) when sorted by flow cytometry of MIA PaCa-2 and PANC-1 pancreatic cancer cells that possess the properties of CSC. A large fraction of these SP cells are CD44 and CD24 positive, are gemcitabine resistant, possess sphere-forming ability, and exhibit increased tumorigenicity, known characteristics of cancer stemness. Increased tumorigenicity and gemcitabine resistance decrease after suppression of uPA. We observe that uPA interacts directly with transcription factors LIM homeobox-2 (Lhx2), homeobox transcription factor A5 (HOXA5), and Hey to possibly promote cancer stemness. uPA regulates Lhx2 expression by suppressing expression of miR-124 and p53 expression by repressing its promoter by inactivating HOXA5. These results demonstrate that regulation of gene transcription by uPA contributes to cancer stemness and clinical lethality.
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Sahin, Ibrahim Halil, Gokce Askan, Joanne F. Chou, Marinela Capanu, Kenneth H. Yu, Olca Basturk, Christine A. Iacobuzio-Donahue y Eileen Mary O'Reilly. "Association of pancreatic cancer stem cells with tumor stroma type." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): e15771-e15771. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15771.
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e15771 Background: Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease with distinct stroma features. Cancer stem cells (CSC) in PDA may express CD44 (C) +/- Epithelial Specific Antigen (E). We investigated the relationship of CSC markers with tumor stroma and clinical outcomes in PDA patients (pts) who had surgical resection. Methods: Pts who underwent PDA resection with IRB #00-032/#06-107 consent between 01/2012-06/2014 at Memorial Sloan Kettering were identified. C and E immunohistochemical (IHC) expression scored as follow: 0, none; 1, 1%–10%; 2, 11%–50%; 3, 51%–80%; 4, 81%–100%. Staining intensity was scored as 0, none; 1, weak; 2, moderate; 3, strong. The total scores (0-12) were averaged and was considered positive when average score > median. Stroma was classified as loose, moderate and dense based on fibroblast content using H&E stain. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier and compared by log-rank test; association between CSC markers and stroma type was assessed by Fisher`s exact test. Results: N = 93 PDA pts identified. PDA with C(+) E(-) had significantly higher loose stroma and PDA with C(-) E(+) and C(-) E(-) had more moderate and dense stroma (p = 0.0033). The number of PDA pts with dense, moderate, and loose stroma was: 11, 31, and 51 respectively. No local recurrence in pts with dense stroma observed and 8/11 had either lung or liver recurrence. Six of 31pts with loose stroma had a local recurrence and 13/31 pts had either liver or lung recurrence. No statistically significant difference in OS and RFS were observed among subgroups (P = 0.089). Median time from relapse to death was: 2, 11.5, 10,5 and months 7 in C+/E-, C-/E+, C+/E+, and C-/E- groups respectively. Conclusions: PDA CSCs appears to have an association with PDA stroma type. We also observed different recurrence patterns among stroma subgroups. Respecting small sample size, these data indicate CSCs may have an important role in stroma differentiation in PDA. CSC markers do not predict OS and RFS, however, resected PDA with C(+) E(-) may have more aggressive behavior following recurrence. [Table: see text]
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Gajate, Consuelo, Odile Gayet, Nicolas A. Fraunhoffer, Juan Iovanna, Nelson Dusetti y Faustino Mollinedo. "Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition". Cancers 13, n.º 23 (5 de diciembre de 2021): 6124. http://dx.doi.org/10.3390/cancers13236124.
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Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+CD24+EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
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Eptaminitaki, Giasemi C., Apostolos Zaravinos, Dimitris Stellas, Maria Panagopoulou, Sevasti Karaliota, Ismini Baltsavia, Ioannis Iliopoulos, Ekaterini Chatzaki, Dimitrios Iliopoulos y Stavroula Baritaki. "Genome-Wide Analysis of lncRNA-mRNA Co-Expression Networks in CD133+/CD44+ Stem-like PDAC Cells". Cancers 15, n.º 4 (7 de febrero de 2023): 1053. http://dx.doi.org/10.3390/cancers15041053.
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Pancreatic ductal adenocarcinoma (PDAC), the second most prevalent gastrointestinal malignancy and the most common type of pancreatic cancer is linked with poor prognosis and, eventually, with high mortality rates. Early detection is seldom, while tumor heterogeneity and microarchitectural alterations benefit PDAC resistance to conventional therapeutics. Although emerging evidence suggest the core role of cancer stem cells (CSCs) in PDAC aggressiveness, unique stem signatures are poorly available, thus limiting the efforts of anti-CSC-targeted therapy. Herein, we report the findings of the first genome-wide analyses of mRNA/lncRNA transcriptome profiling and co-expression networks in PDAC cell line-derived CD133+/CD44+ cells, which were shown to bear a CSC-like phenotype in vitro and in vivo. Compared to CD133−/CD44− cells, the CD133+/CD44+ population demonstrated significant expression differences in both transcript pools. Using emerging bioinformatic tools, we performed lncRNA target coding gene prediction analysis, which revealed significant Gene Ontology (GO), pathway, and network enrichments in many dyregulated lncRNA nearby (cis or trans) mRNAs, with reported involvement in the regulation of CSC phenotype and functions. In this context, the construction of lncRNA/mRNA networks by ingenuity platforms identified the lncRNAs ATF2, CHEK1, DCAF8, and PAX8 to interact with “hub” SC-associated mRNAs. In addition, the expressions of the above lncRNAs retrieved by TCGA-normalized RNAseq gene expression data of PAAD were significantly correlated with clinicopathological features of PDAC, including tumor grade and stage, nodal metastasis, and overall survival. Overall, our findings shed light on the identification of CSC-specific lncRNA signatures with potential prognostic and therapeutic significance in PDAC.
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Qorri, Bessi, Reza Bayat Mokhtari, William W. Harless y Myron R. Szewczuk. "Repositioning of Old Drugs for Novel Cancer Therapies: Continuous Therapeutic Perfusion of Aspirin and Oseltamivir Phosphate with Gemcitabine Treatment Disables Tumor Progression, Chemoresistance, and Metastases". Cancers 14, n.º 15 (23 de julio de 2022): 3595. http://dx.doi.org/10.3390/cancers14153595.
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Metastatic pancreatic cancer has an invariably fatal outcome, with an estimated median progression-free survival of approximately six months employing our best combination chemotherapeutic regimens. Once drug resistance develops, manifested by increased primary tumor size and new and growing metastases, patients often die rapidly from their disease. Emerging evidence indicates that chemotherapy may contribute to the development of drug resistance through the upregulation of epithelial–mesenchymal transition (EMT) pathways and subsequent cancer stem cell (CSC) enrichment. Neuraminidase-1 (Neu-1) regulates the activation of several receptor tyrosine kinases implicated in EMT induction, angiogenesis, and cellular proliferation. Here, continuous therapeutic targeting of Neu-1 using parenteral perfusion of oseltamivir phosphate (OP) and aspirin (ASA) with gemcitabine (GEM) treatment significantly disrupts tumor progression, critical compensatory signaling mechanisms, EMT program, CSC, and metastases in a preclinical mouse model of human pancreatic cancer. ASA- and OP-treated xenotumors significantly inhibited the metastatic potential when transferred into animals.
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Jeng, Kuo-Shyang, Chiung-Fang Chang y Shu-Sheng Lin. "Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments". International Journal of Molecular Sciences 21, n.º 3 (23 de enero de 2020): 758. http://dx.doi.org/10.3390/ijms21030758.
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During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
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Berg, Anastasia L., Ashley Rowson-Hodel, Michelle Hu, Michael Keeling, Hao Wu, Kacey VanderVorst, Jenny J. Chen et al. "The Cationic Amphiphilic Drug Hexamethylene Amiloride Eradicates Bulk Breast Cancer Cells and Therapy-Resistant Subpopulations with Similar Efficiencies". Cancers 14, n.º 4 (14 de febrero de 2022): 949. http://dx.doi.org/10.3390/cancers14040949.
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The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species but acts poorly toward non-transformed cells derived from multiple tissues. Here, we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate, and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Our observations expose a key vulnerability intrinsic to cancer stem cells and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.
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Rodriguez-Aznar, Eva, Lisa Wiesmüller, Bruno Sainz y Patrick C. Hermann. "EMT and Stemness—Key Players in Pancreatic Cancer Stem Cells". Cancers 11, n.º 8 (8 de agosto de 2019): 1136. http://dx.doi.org/10.3390/cancers11081136.
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Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state promotes migration and survival both during development and in cancer progression. When re-activated in pathological contexts such as cancer, this type of developmental process confers additional stemness properties to specific subsets of cells. Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem-like features that are responsible for the propagation of the tumor as well as therapy resistance and cancer relapse, but also for circulating tumor cell release and metastasis. In support of this concept, EMT transcription factors generate cells with stem cell properties and mediate chemoresistance. However, their role in pancreatic ductal adenocarcinoma metastasis remains controversial. As such, a better characterization of CSC populations will be crucial in future development of therapies targeting these cells. In this review, we will discuss the latest updates on the mechanisms common to pancreas development and CSC-mediated tumor progression.
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Dong, Liangchao, Weiwei Li y Xiaoli Zhang. "Knockdown of pancreatic adenocarcinoma upregulated factor (PAUF) suppresses proliferation, migration, invasion, and cancer stem cell properties in lung cancer cells". Tropical Journal of Pharmaceutical Research 20, n.º 3 (17 de enero de 2022): 459–65. http://dx.doi.org/10.4314/tjpr.v20i3.3.
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Purpose: To investigate the role of pancreatic adenocarcinoma up-regulated factor (PAUF) in lung cancer.
Method: Proliferation of lung cancer cell lines (A549 and H1299) was determined using MTS and Edu staining assays. Wound healing and transwell assays were performed to evaluate cell migration and invasion abilities. Lung cancer stem cell (CSC) marker expressions, including CD133, CD44, ALDH1, SOX2, and Oct4, were determined by western blot assay.
Results: Knockdown of PAUF significantly inhibited A459 and H1299 cell proliferation (p < 0.01). The wound healing and transwell assay results indicated that depletion of PAUF markedly suppressed H1299 and A549 cell migration and invasion, compared with the control cells (p < 0.01). Knockdown of PAUF reduced distinct CSC marker expression, suggesting inhibition of CSC phenotypes, and reduced phosphorylated focal adhesion kinase (FAK), phosphorylated Src, and phosphorylated extracellular signal-regulated kinase (ERK), but not total FAK, Src, and ERK. These results suggested that knockdown of PAUF deactivated the FAK/Src/ERK signal pathway.
Conclusion: Knockdown of PAUF inhibits lung cancer cell proliferation, migration, invasion, and CSC properties via deactivation of FAK/Src/ERK signal pathway. These results may provide a novel strategy for the development of lung cancer therapeutics.
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Garg, Rachana, Laleh Melstorm, Jianjun Chen, Chuan He y Ajay Goel. "Abstract 5711: Targeting FTO suppresses pancreatic carcinogenesis via cancer stem cell maintenance". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 5711. http://dx.doi.org/10.1158/1538-7445.am2022-5711.
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Abstract Background: Pancreatic cancer (PC) remains a lethal disease worldwide and is estimated to become the 2nd leading cause of cancer-related deaths in the United States by 2030. Recently, existence of cancer stem cells (CSC) has been reported in several malignancies, including PC and have been considered as seeds for cancer initiating cells. However, the molecular mechanism governing the maintenance of CSC traits and their self-renewal remain unclear. Upregulated expression of fat mass and obesity-associated protein (FTO), which demethylates N6-methyladenosine (the most prevalent eukaryotic RNA modification), has been associated with cancer progression of various types. Nevertheless, our current understanding on the role of FTO in modulating biological processes relevant to PC is in infancy. Methods: In this study, we first analyzed and compared the FTO expression in various PC cells vs normal pancreatic ductal epithelial (HPDE) cells. We then depleted FTO in PC cells using lentiviral-mediated and pharmacological inhibitor (CS1) approaches and analyzed the effects on cell growth, proliferation, apoptosis, cell cycle, migration, invasion, epithelial-mesenchymal transition, CSC growth and self-renewal, and xenograft tumor formation. Results: We found that PC cells expressed markedly higher mRNA and protein levels of FTO compared to HPDE cells. FTO depleted PC cells showed impaired growth in both the solid and semi-solid medium, and also a G1 phase cell cycle arrest which correlated with the increment in the expression of CDK inhibitors: p21cip1 and p27kip1. FTO loss in the PC cells also led to an increase in early apoptotic cell population with a concomitant increase in the expression of caspase 3 and 9. Of note, FTO depleted PC cells displayed marked delay in the wound closure and reduced capabilities to invade through matrigel. This further corroborated with the enhanced expression levels of epithelial (E-cadherin) and decrease in the mesenchymal (N-cadherin, vimentin, and fibronectin) markers. Mechanistically, MET in FTO depleted cells correlated with impaired tumor sphere formation and reduced expression of markers of cancer stemness (CD44, NanoG, Sox2, ALDH1, and CD133). Replating of single cell derived from these spheroids revealed that FTO loss hampered the secondary spheres formation; thus, FTO is necessary for spheroid formation, their maintenance and self-renewal potential of CSC. Additionally, FTO loss in PC cells led to delayed as well as decreased tumor growth in nude mice. Tumor extracts from FTO-depleted xenografts displayed induction of apoptosis, decreased expression of proliferation marker Ki67, and a MET phenotype. Conclusion: Through a comprehensive mechanistic analysis we explicitly demonstrate the biological and functional significance of FTO in governing PC tumorigenesis and maintenance of CSC; thus, targeting FTO may represent an attractive therapeutic approach for PC. Citation Format: Rachana Garg, Laleh Melstorm, Jianjun Chen, Chuan He, Ajay Goel. Targeting FTO suppresses pancreatic carcinogenesis via cancer stem cell maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5711.
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Lorico, Aurelio y Germana Rappa. "Phenotypic Heterogeneity of Breast Cancer Stem Cells". Journal of Oncology 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/135039.
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Many types of tumors are organized in a hierarchy of heterogeneous cell populations, with only a small proportion of cancer stem cells (CSCs) capable of sustaining tumor formation and growth, giving rise to differentiated cells, which form the bulk of the tumor. Proof of the existence of CSC comes from clinical experience with germ-cell cancers, where the elimination of a subset of undifferentiated cells can cure patients (Horwich et al., 2006), and from the study of leukemic cells (Bonnet and Dick, 1997; Lapidot et al., 1994; and Yilmaz et al., 2006). The discovery of CSC in leukemias as well as in many solid malignancies, including breast carcinoma (Al-Hajj et al. 2003; Fang et al., 2005; Hemmati et al., 2003; Kim et al., 2005; Lawson et al., 2007; Li et al., 2007; Ricci-Vitiani et al., 2007; Singh et al., 2003; and Xin et al., 2005), has suggested a unifying CSC theory of cancer development. The reported general insensitivity of CSC to chemotherapy and radiation treatment (Bao et al., 2006) has suggested that current anticancer drugs, which inhibit bulk replicating cancer cells, may not effectively inhibit CSC. The clinical relevance of targeting CSC-associated genes is supported by several recent studies, including CD44 targeting for treatment of acute myeloid leukemia (Jin et al., 2006), CD24 targeting for treatment of colon and pancreatic cancer (Sagiv et al., 2008), and CD133 targeting for hepatocellular and gastric cancer (Smith et al., 2008). One promising approach is to target CSC survival signaling pathways, where leukemia stem cell research has already made some progress (Mikkola et al., 2010).
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Ferrara, Benedetta, Erica Dugnani, Valeria Sordi, Valentina Pasquale, Silvia Pellegrini, Michele Reni, Gianpaolo Balzano y Lorenzo Piemonti. "A Comprehensive Characterization of Stemness in Cell Lines and Primary Cells of Pancreatic Ductal Adenocarcinoma". International Journal of Molecular Sciences 23, n.º 18 (14 de septiembre de 2022): 10663. http://dx.doi.org/10.3390/ijms231810663.
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The aim of this study is to provide a comprehensive characterization of stemness in pancreatic ductal adenocarcinoma (PDAC) cell lines. Seventeen cell lines were evaluated for the expression of cancer stem cell (CSC) markers. The two putative pancreatic CSC phenotypes were expressed heterogeneously ranging from 0 to 99.35% (median 3.46) for ESA+CD24+CD44+ and 0 to 1.94% (median 0.13) for CXCR4+CD133+. Cell lines were classified according to ESA+CD24+CD44+ expression as: Low-Stemness (LS; <5%, n = 9, median 0.31%); Medium-Stemness (MS; 6–20%, n = 4, median 12.4%); and High-Stemness (HS; >20%, n = 4, median 95.8%) cell lines. Higher degree of stemness was associated with in vivo tumorigenicity but not with in vitro growth kinetics, clonogenicity, and chemo-resistance. A wide characterization (chemokine receptors, factors involved in pancreatic organogenesis, markers of epithelial–mesenchymal transition, and secretome) revealed that the degree of stemness was associated with KRT19 and NKX2.2 mRNA expression, with CD49a and CA19.9/Tie2 protein expression, and with the secretion of VEGF, IL-7, IL-12p70, IL-6, CCL3, IL-10, and CXCL9. The expression of stem cell markers was also evaluated on primary tumor cells from 55 PDAC patients who underwent pancreatectomy with radical intent, revealing that CXCR4+/CD133+ and CD24+ cells, but not ESA+CD24+CD44+, are independent predictors of mortality.
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Durko, L., W. Wlodarski, O. Stasikowska-Kanicka, M. Wagrowska-Danilewicz, M. Danilewicz, P. Hogendorf, J. Strzelczyk y E. Malecka-Panas. "Expression and Clinical Significance of Cancer Stem Cell Markers CD24, CD44, and CD133 in Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis". Disease Markers 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/3276806.
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Cancer stem cells (CSC) play an important role in pancreatic carcinogenesis and prognosis. The study aimed at examining the expression of CD24, CD44, and CD133 in human PDAC and CP in order to evaluate its clinicopathological correlations and the clinical significance. Surgical specimens from 23 patients with PDAC and 15 patients with chronic pancreatitis after pancreatic resection were stained with CD24, CD44, and CD133 antibodies. The intensity of staining was scored from 0 (negative) to 3 (strongly positive). Results. Mean CD24 staining score in PDAC was 1.38 ± 0.76 and was significantly higher than that in CP: 0.70 ± 0.53 (p<0.01); CD44 score in PDAC was 2.23 ± 0.42 and was significantly higher than that in CP: 1.87 ± 0.55 (p<0.05); CD133 score 0.93 ± 0.58 was not different from CP: 0.71 ± 0.43 (p>0.05). CD44 immunoreactivity was significantly higher (p<0.05) in pT1 and pT2 patients together as regards pT3: 2.45 ± 0.37 versus 2.06 ± 0.38 as well as in N0 patients compared to N1 patients: 2.5 ± 0.38 versus 2.04 ± 0.34. Conclusions. CD24 and CD44 are upregulated in human pancreatic cancer compared to chronic pancreatitis. CD44 immunoreactivity decreases with the tumor advancement and may represent the negative PDAC prognostic factor. Each CSC marker was differently related to PDAC advancement. CD133 may lack clinical significance in PDAC.
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Dong, Ruochen, Ping Chen y Qi Chen. "Extract of the Medicinal Plant Pao Pereira Inhibits Pancreatic Cancer Stem-Like Cell In Vitro and In Vivo". Integrative Cancer Therapies 17, n.º 4 (9 de julio de 2018): 1204–15. http://dx.doi.org/10.1177/1534735418786027.
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Pancreatic cancers are enriched with cancer stem-like cells (CSCs), which are resistant to chemotherapies, and responsible for tumor metastasis and recurrence. Here, we investigated the extract of a medicinal plant Pao Pereira (Pao) for its activity against pancreatic CSCs. Pao inhibited overall proliferation of human pancreatic cancer cell lines with IC50 ranging from 125 to 325 μg/mL and had limited cytotoxicity to normal epithelial cells. Pancreatic CSC population, identified using surface markers CD24+ CD44+ EpCam+ or tumor spheroid formation assay, was significantly reduced, with IC50s of ~100 μg/mL for 48 hours treatment, and ~27 μg/mL for long-term treatment. Nuclear β-catenin levels were decreased, suggesting suppression of Wnt/β-catenin signaling pathway. In vivo, Pao at 20 mg/kg, 5 times/week gavage, significantly reduced tumorigenicity of PANC-1 cells in immunocompromised mice, indicating inhibition of CSCs in vivo. Further investigation is warranted in using Pao as a novel treatment targeting pancreatic CSCs.
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Capodanno, Y., F. O. Buishand, L. Y. Pang, J. Kirpensteijn, J. A. Mol y D. J. Argyle. "Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells". Endocrine-Related Cancer 25, n.º 2 (febrero de 2018): 131–44. http://dx.doi.org/10.1530/erc-17-0415.
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Insulinomas (INS) are the most common neuroendocrine pancreatic tumours in humans and dogs. The long-term prognosis for malignant INS is still poor due to a low success rate of the current treatment modalities, particularly chemotherapy. A better understanding of the molecular processes underlying the development and progression of INS is required to develop novel targeted therapies. Cancer stem cells (CSCs) are thought to be critical for the engraftment and chemoresistance of many tumours, including INS. This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies. Highly invasive and tumourigenic human and canine INS CSC-like cells were successfully isolated. These cells expressed stem cell markers (OCT4,SOX9, SOX2, CD133 and CD34), exhibited greater resistance to 5-fluorouracil (5-FU) and demonstrated a more invasive and tumourigenic phenotypein vivocompared to bulk INS cells. Here, we demonstrated that Notch-signalling-related genes (NOTCH2andHES1)were overexpressed in INS CSC-like cells. Protein analysis showed an active NOTCH2-HES1 signalling in INS cell lines, especially in cells resistant to 5-FU. Inhibition of the Notch pathway, using a gamma secretase inhibitor (GSI), enhanced the sensitivity of INS CSC-like cells to 5-FU. When used in combination GSI and 5-FU, the clonogenicityin vitroand the tumourigenicityin vivoof INS CSC-like cells were significantly reduced. These findings suggested that the combined strategy of Notch signalling inhibition and 5-FU synergistically attenuated enriched INS CSC populations, providing a rationale for future therapeutic exploitation.
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Ikezono, Yu, Hironori Koga, Jun Akiba, Mitsuhiko Abe, Takafumi Yoshida, Fumitaka Wada, Toru Nakamura et al. "Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1". Molecular Cancer Research 15, n.º 6 (8 de febrero de 2017): 744–52. http://dx.doi.org/10.1158/1541-7786.mcr-16-0285.
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Smigiel, Jacob M., Neetha Parameswaran y Mark W. Jackson. "Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer". Molecular Cancer Research 15, n.º 4 (4 de enero de 2017): 478–88. http://dx.doi.org/10.1158/1541-7786.mcr-16-0337.
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Tiwary, Kanishka, Anton Lahusen, Syeda Inaas, Stefanie Hauff, Karolin Walter, Alexander Kleger, Thomas Seufferlein, Bruno Sainz y Patrick Christian Hermann. "Abstract B035: CXCL12 / CXCR4 signaling enhances and sustains migrating cancer stem cells via BMI1 in pancreatic ductal adenocarcinomas". Cancer Research 83, n.º 2_Supplement_2 (15 de enero de 2023): B035. http://dx.doi.org/10.1158/1538-7445.metastasis22-b035.
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Abstract Pancreatic cancer is a fatal disease and is one of the most aggressive and metastatic malignancies worldwide. The dissemination of tumor cells is the prerequisite of metastases and correlates with a loss of epithelial differentiation and the acquisition of a migratory phenotype, a hallmark of malignant tumor progression. Migrating cancer stem cells (miCSCs) characterized by CD133+ and CXCR4+ expression play a pivotal role in malignant tumor formation, have been reported to form the invasive front of the metastasis and in silico analysis showed that both CSCs and miCSCs are significantly upregulated in PDAC. However, the regulatory pattern maintaining these CSCs and especially miCSCs in PDAC remains widely elusive. Thus, this study further helps to unravel pathways responsible for maintenance of CSC (CD133+) and miCSC (CD133+ CXCR4+) population. To identify key signaling pathways responsible for both CSCs and miCSCs maintenance, we first generated a protein-protein interaction network using STRING database. Afterwards, we validated these signaling pathway(s) involved in aiding CSC and miCSC population by performing shRNA mediated knockdown of key signaling proteins in different patient-derived pancreatic cancer cell lines. Moreover, we interrogated the involvement of the tumor-stroma crosstalk in the regulation of these pathways by co-culturing tumor cells with pancreatic stellate cells. Protein-protein interaction network incorporating relevant factors involved in EMT, stemness, as well as SHH, NF-kB and AKT signaling pathway identified a strong link between the CXCL12/CXCR4 signaling axis and BMI1. Migration assay, sphere formation assay and western blot upon shRNA mediated knockdown of either CXCR4 and/or BMI1 ascertained BMI1 as a key player downstream of the CXCL12/CXCR4 axis to mechanistically effect both EMT and stemness. Pathway focused gene expression analysis as well as ELISA and immunofluorescence for CXCL12 and actin filaments, respectively, revealed the indispensable nature of tumor-stroma crosstalk on promoting CSC and miCSC population through the chemokine CXCL12. In addition, co-culture systems revealed that particularly pancreatic stellate cells play a significant role in maintaining both CSCs and miCSCs population as well as their characteristic phenotype including but not limited to chemotherapy resistance. Taken together, our results obtained in this study established mechanistically that the CXCL12/CXCR4 signaling pathway driven by tumor-stroma crosstalk not only enhances but also maintains both CSCs and miCSCs in pancreatic ductal adenocarcinomas through BMI1 ultimately promoting metastases and therapeutic resistance. Citation Format: Kanishka Tiwary, Anton Lahusen, Syeda Inaas, Stefanie Hauff, Karolin Walter, Alexander Kleger, Thomas Seufferlein, Bruno Sainz Jr., Patrick Christian Hermann. CXCL12 / CXCR4 signaling enhances and sustains migrating cancer stem cells via BMI1 in pancreatic ductal adenocarcinomas [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B035.
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Lee, Cheong J., Joseph Dosch y Diane M. Simeone. "Pancreatic Cancer Stem Cells". Journal of Clinical Oncology 26, n.º 17 (10 de junio de 2008): 2806–12. http://dx.doi.org/10.1200/jco.2008.16.6702.
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Cellular heterogeneity in cancer was observed decades ago by studies in mice which showed that distinct subpopulations of cells within a tumor mass are capable of driving tumorigenesis. Conceptualized from this finding was the stem-cell hypothesis for cancer, which suggests that only a specific subset of cancer cells within each tumor is responsible for tumor initiation and propagation, termed tumor initiating cells or cancer stem cells (CSCs). Recent data has been provided to support the existence of CSCs in human blood cell–derived cancers and solid organ tumors of the breast, brain, prostate, colon, and skin. Study of human pancreatic cancers has also revealed a specific subpopulation of cancer cells that possess the characteristics of CSCs. These pancreatic cancer stem cells express the cell surface markers CD44, CD24, and epithelial-specific antigen, and represent 0.5% to 1.0% of all pancreatic cancer cells. Along with the properties of self-renewal and multilineage differentiation, pancreatic CSCs display upregulation of important developmental genes that maintain self-renewal in normal stem cells, including Sonic hedgehog (SHH) and BMI-1. Signaling cascades that are integral in tumor metastasis are also upregulated in the pancreatic CSC. Understanding the biologic behavior and the molecular pathways that regulate growth, survival, and metastasis of pancreatic CSCs will help to identify novel therapeutic approaches to treat this dismal disease.
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Cannone, Stefania, Maria Raffaella Greco, Tiago M. A. Carvalho, Helene Guizouarn, Olivier Soriani, Daria Di Molfetta, Richard Tomasini, Katrine Zeeberg, Stephan Joel Reshkin y Rosa Angela Cardone. "Cancer Associated Fibroblast (CAF) Regulation of PDAC Parenchymal (CPC) and CSC Phenotypes Is Modulated by ECM Composition". Cancers 14, n.º 15 (31 de julio de 2022): 3737. http://dx.doi.org/10.3390/cancers14153737.
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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancers, having one of the lowest five-year survival rates. One of its hallmarks is a dense desmoplastic stroma consisting in the abnormal accumulation of extracellular matrix (ECM) components, especially Collagen I. This highly fibrotic stroma embeds the bulk cancer (parenchymal) cells (CPCs), cancer stem cells (CSCs) and the main producers of the stromal reaction, the Cancer Associated Fibroblasts (CAFs). Little is known about the role of the acellular ECM in the interplay of the CAFs with the different tumor cell types in determining their phenotypic plasticity and eventual cell fate. Methods: Here, we analyzed the role of ECM collagen I in modulating the effect of CAF-derived signals by incubating PDAC CPCs and CSCs grown on ECM mimicking early (low collagen I levels) and late (high collagen I levels) stage PDAC stroma with conditioned medium from primary cultured CAFs derived from patients with PDAC in a previously described three-dimensional (3D) organotypic model of PDAC. Results: We found that CAFs (1) reduced CPC growth while favoring CSC growth independently of the ECM; (2) increased the invasive capacity of only CPCs on the ECM mimicking the early tumor; and (3) favored vasculogenic mimicry (VM) especially of the CSCs on the ECM mimicking an early tumor. Conclusions: We conclude that the CAFs and acellular stromal components interact to modulate the tumor behaviors of the PDAC CPC and CSC cell types and drive metastatic progression by stimulating the phenotypic characteristics of each tumor cell type that contribute to metastasis.
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Noorani, Sara, Shannon R. Nelson, Neil T. Conlon, Justine Meiller, Ekaterina Shcheglova, Alice Usai, Jojanneke Stoof et al. "Pancreatic Cancer 3D Cell Line Organoids (CLOs) Maintain the Phenotypic Characteristics of Organoids and Accurately Reflect the Cellular Architecture and Heterogeneity In Vivo". Organoids 1, n.º 2 (12 de diciembre de 2022): 168–83. http://dx.doi.org/10.3390/organoids1020013.
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Pancreatic cancer is a highly lethal disease. Therapeutic resistance to chemotherapy is a major cause of treatment failure and recurrence in pancreatic cancer. Organoids derived from cancer stem cells (CSC) are promising models for the advancement of personalised therapeutic responses to inform clinical decisions. However, scaling-up of 3D organoids for high-throughput screening is time-consuming and costly. Here, we successfully developed organoid-derived cell lines (2.5D) from 3D organoids; the cells were then expanded and recapitulated back into organoids known as cell line organoids (CLOs). The 2.5D lines were cultured long term into 2D established cell lines for downstream comparison analysis. Experimental characterisation of the models revealed that the proliferation of CLOs was slightly faster than that of parental organoids. The therapeutic response to chemotherapeutic agents in 3D CLOs and organoids showed a similar responsive profile. Compared to 3D CLOs and organoids, 2D cell lines tended to be less responsive to all the drugs tested. Stem cell marker expression was higher in either 3D CLOs or organoids compared to 2D cell lines. An in vivo tumorigenicity study found CLOs form tumours at a similar rate to organoids and retain enhanced CSC marker expression, indicating the plasticity of CSCs within the in vivo microenvironment.
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Gromisch, Christopher, Matthew Stannard Gromisch, Mark Grinstaff, Victoria L. M. Herrera y Nelson Ruiz-Opazo. "Humanized anti-DEspR monoclonal antibody to improve overall survival in xenograft pancreatic peritoneal carcinomatosis nude rat model." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): e16262-e16262. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e16262.
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e16262 Background: Pancreatic adenocarcinoma (PDAC) with peritoneal carcinomatosis (PPC) has the worst median overall survival (mOS) among all PDAC metastasis. Novel therapeutic approaches are needed for PPC. The Dual Endothelin-1/VEGF-signal-peptide Receptor (DEspR) is a cell surface receptor which regulates PDAC tumor cell and cancer stem-like cell (CSC) anoikis resistance, tumorigenicity, and tumoral angiogenesis. To translate these findings into a novel anti-cancer therapy, we evaluated the efficacy, empirical safety, pharmacokinetics, and pharmacodynamics of a recombinant, humanized, anti-DEspR hinge-stabilized IgG4S228P monoclonal antibody, hu-6g8, in a PPC xenograft tumor nude rat model. Methods: We used a Panc1 CSC-derived xenograft tumor model of PPC developed via intraperitoneal injection of two million Panc1 CSCs functionally isolated for anoikis resistance. Isolated CSCs had variable DEspR expression, thus modeling CSC-heterogeneity. For efficacy studies, PPC-rats were randomized to receive a single intravenous injection of either 3mg/kg or 15mg/kg hu-6g8, 100mg/kg gemcitabine, or saline, given 3 weeks after CSC injection with palpable PPC tumors. Blood samples were collected to monitor for hematological adverse events (AEs) and vital organs were collected to evaluate for hu-6g8-induced apoptosis. Pharmacokinetics was assessed in a separate study cohort by sequential blood draws after rats received a single dose of 3 mg/kg or 15 mg/kg hu-6g8. In a 3rd cohort, pharmacodynamics were assessed by vital organ collection and immunohistochemistry after rats received either a single-iv injection of 3mg/kg hu-6g8 or IgG4 isotype control. Results: Single dose 15 mg/kg hu-6g8 treatment significantly improved median overall survival (189 days, n = 0.0007) with 3 mg/kg hu-6g8 being comparable to 100 mg/kg gemcitabine (92 vs 115 days, n = 0.62). No hematological AEs were observed in hu-6g8 treated rats, and there was no evidence of increased apoptosis by hu-6g8 in normal tissues by immunohistochemistry of activated Caspase-3. Hu-6g8 demonstrated an average elimination half-life of 46.1 hrs in a two-compartment model. Biodistribution of the antibody showed predominant uptake, albeit heterogenous, and induction of activated caspase 3+ apoptosis in the peritoneal tumors by 24-hours with minimal off-target binding. Conclusions: Treatment with monoclonal hu-6g8 significantly improved survival in a model of PCC with excellent tumor specificity and minimal off-target effect.
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Arasanz, Hugo, Carlos Hernández, Ana Bocanegra, Luisa Chocarro, Miren Zuazo, Maria Gato, Karina Ausin et al. "Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition". Cancers 12, n.º 8 (5 de agosto de 2020): 2181. http://dx.doi.org/10.3390/cancers12082181.
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Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.
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Askan, Gokce, Ibrahim Halil Sahin, Marinela Capanu, Mesruh Turkekul, Kenneth H. Yu, Maeve Aine Lowery, Olca Basturk, Christine Iacobuzio-Donahue y Eileen Mary O'Reilly. "Do pancreas cancer stem cells play crucial role in survival outcome?" Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): e15721-e15721. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15721.
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e15721 Background: Recent studies indicate that pancreatic cancer stem cells (CSC) may predict disease behavior and survival outcomes of pancreatic ductal adenocarcinomas (PDACs) patients (pts). Several CSC markers have been reported in PDAC (Fitzgerald, TL, 2014). We herein evaluated the impact of CSC markers including CD44 and Epithelial Specific Antigen (ESA) on survival outcome of PDAC pts who had liver or lung metastasis after initial surgical resection (IR). Methods: Clinicopathologic features and survival of 59 PDACs were analyzed. Pts with IRB approval, and whom had available primary tumor tissue, were included. All neoplasms were immuno labeled with CD44 and ESA. Staining intensity was scored as weak (1), moderate (2), strong (3), while the staining pattern was scored as: few (1), patchy (2), and diffuse (3). The expression for CD44 and ESA was accepted positive if total score ≥4. Time from relapse to death (TRD) was estimated using the Kaplan-Meier method censoring patients that were alive at the last follow up. Survival curves were compared using the log-rank test Results: Of 59 pts, 42 (71 %) had liver, 10 (17%) had lung and 7 (12%) had both liver and lung metastasis. M/F = 34/25; mean age = 64.2 (range, 34-90). Patients were subcategorized as follows; thirteen cases were CD44 (+)/ESA (-) (group1) and 13 were CD44 (-)/ESA (+) (group 2). Eight (61.5%) of group 1 tumors and 2 (15.3%) of group 2 were poorly differentiated. At last follow-up, except one with 63 months survival, all pts died of disease with 23.3 months (range, 3-67) median OS. No significant difference in TRD was observed between group 1 (6.9 months) and 2 (13.8 months) (p = 0.62). However, we observed group 1 tumors had worse OS (12 months) compared to group 2 (36 months). Conclusions:A worse outcome trend was observed for pts with CD44 (+)/ESA (-), albeit not statistically significant and likely limited by small numbers. Further studies are warranted to evaluate the robustness of this observation.
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Shen, Pu, Zheng, Ma, Qin, Jiang y Li. "Differentially Expressed microRNAs in MIA PaCa-2 and PANC-1 Pancreas Ductal Adenocarcinoma Cell Lines are Involved in Cancer Stem Cell Regulation". International Journal of Molecular Sciences 20, n.º 18 (10 de septiembre de 2019): 4473. http://dx.doi.org/10.3390/ijms20184473.
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and thus better understanding of its molecular pathology is crucial for us to devise more effective treatment of this deadly disease. As cancer cell line remains a convenient starting point for discovery and proof-of-concept studies, here we report the miRNA expression characteristics of two cell lines, MIA PaCa-2 and PANC-1, and discovered three miRNAs (miR-7-5p, let-7d, and miR-135b-5p) that are involved in cancer stem cells (CSCs) suppression. After transfection of each miRNA’s mimic into PANC-1 cells which exhibits higher stemness feature than MIA-PaCa-2 cells, partial reduction of CSC surface markers and inhibition of tumor sphere formation were observed. These results enlighten us to consider miRNAs as potential therapeutic agents for pancreatic cancer patients via specific and effective inhibition of CSCs.
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Wang, Shuai, Shuai Huang y Yu Ling Sun. "Epithelial-Mesenchymal Transition in Pancreatic Cancer: A Review". BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/2646148.
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies and is characterized by its insensitivity to current therapy. The invasion and metastasis of solid tumors such as PDAC are complex processes involving many factors. Recent insights into the role of cancer stem cells (CSCs) and the epithelial-mesenchymal transition (EMT) in tumorigenesis have increased the knowledge base and highlighted new therapeutic targets of this disease. The process of EMT is regulated by a complex network of cytokines, transcription factors, growth factors, signaling pathways, and the tumor microenvironment, exhibiting CSC-like properties. The transition of solid cancer cells from an epithelial to a mesenchymal phenotype increases their migratory and invasive properties, thus promoting metastasis. In PDAC, the exact influence of EMT on the biological behaviors of cancer cells and its impact on clinical therapy remain controversial, but the therapeutic strategy of combining EMT inhibition with chemotherapy deserves attention. Alternatively, anti-inflammatory therapy that targets the interaction between inflammation and EMT is a valid strategy for treating the premalignant stage of tumor progression. In this review, we summarize the latest research on EMT and the potential relationship between EMT and PDAC.
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Arima, K., T. Ishimoto, M. Ohmuraya, H. Okabe, Y. Kitano, K. Yamamura, T. Kaida et al. "20P Verification of mechanism that CSC markers are implicated in poor prognosis for pancreatic ductal adenocarcinoma". Annals of Oncology 27 (diciembre de 2016): ix6. http://dx.doi.org/10.1016/s0923-7534(21)00182-4.
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Valle, Sandra, Laura Martin-Hijano, Sonia Alcalá, Marta Alonso-Nocelo y Bruno Sainz Jr. "The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer". Cancers 10, n.º 2 (26 de enero de 2018): 33. http://dx.doi.org/10.3390/cancers10020033.
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Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.
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Joshi, Prashant J., Ayesha Chawla, Patrick Memari, John Stansfield, Michael Idowu, Adam Sima y Steven R. Grossman. "Role of C terminal binding proteins (CtBP) in pancreatic adenocarcinoma (PDAC)." Journal of Clinical Oncology 36, n.º 4_suppl (1 de febrero de 2018): 320. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.320.
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320 Background: Overexpression of the oncogenic transcription factors CtBP1 and 2 is common and associated with poor prognosis in ovarian, breast and prostate cancer. CtBP2 drives tumor progression through promotion of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) activity. Frequent early metastasis observed in PDAC may depend on EMT and CSC activity, prompting us to investigate the prognostic significance of CtBP1/2 in PDAC. In parallel, we determined the oncogenic contribution of CtBP2 to PDAC utilizing a transgenic KRAS mutant mouse PDAC model (CKP) that incorporated heterozygous loss of the Ctbp2 gene (CKP2). Methods: Immunohistochemistry (IHC) using CtBP1/2 antibodies was performed on 69 cases of resected PDAC from VCU Health for the period 2005-16. Clinical data included stage (84% stage 1/2; 16% stage 3/4), initial CA19-9 level, and overall survival. IHC stains were assigned an Allred score (sum of intensity and proportion) by two independent pathologists with a scale from 0-8. Cox Proportional Hazard survival models were fit for CtBP1/2 staining vs. survival. CtBP1/2 correlation with stage and CA19-9 level was tested by ANOVA. CKP mice were bred to Ctbp2 +/- mice, and survival of cohorts (n = 10 each) of CKP vs. CKP2 mice was analyzed by log-rank analysis of Kaplan-Meier survival curves. Results: CtBP1 and 2 expression was uniformly high (7-8) across all cases, including stage 1/2. Thus, no statistically significant survival difference could be derived based on CtBP1/2 expression [CtBP1 HR 1.03 (0.67-1.41) p 0.92, CtBP2 HR 0.75 (0.39-1.43) p 0.31], and no significant association of CtBP1/2 was seen with stage or CA19-9. Suggesting a possible contribution of CtBP2 in human PDAC, Ctbp2 knockout in CKP2 mice improved median survival (9.5 vs. 8.1 weeks, p < 0.05), decreased mean tumor weight (750 mg vs. 400 mg, p < 0.05), and also abrogated peritoneal metastases and ascites normally seen in 100% of CKP mice. Conclusions: While uniformly high CtBP expression in PDAC subverts prognostic use, CtBP may play a pathogenic role, as CKP2 mice exhibited improved survival, lower tumor burden and no peritoneal spread. Our data supports further study of CtBP inhibition as a potential therapeutic strategy in PDAC.
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Herrera, Victoria L. M., Glaiza L. A. Tan, Ann Marie Moran, Kristine A. Pasion, Julius L. Decano y Nelson Ruiz-Opazo. "Dual endothelin-1/VEGFsp receptor (DEspR): Common target on tumor vascular endothelial cells (TVECs), tumor cells (TCs), and cancer stem cells (CSCs) in glioblastoma and pancreatic cancer." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): e13574-e13574. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13574.
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e13574 Background: New therapies are needed for glioblastoma (GBM) and pancreatic adenocarcinoma (PCa), given their low survival rates. To address this mandate, we tested the hypothesis that inhibition of DEspR, as a common target on TVECs, TCs, and CSCs, can affect multiple key steps in metastasis: angiogenesis, invasiveness, anoikis resistance. Methods: Various analyses were performed: co-immunostaining of tumor tissue and cancer cell lines from PCa and GBM using anti-CD133 and anti-DEspR mAbs; in vitro anti-DEspR mAb inhibition of angiogenesis and TC invasiveness; isolation, functional validation, and DEspR immunostaining of CSCs from PCa (Panc1) and GBM (U87) cell lines; DEspR inhibition of Panc1- and U87-derived CSC tumorsphere formation and CSC-enriched xenograft tumor growth in nude rats respectively; and phosphoproteome analysis of DEspR signaling. Results: In PCa and GBM, we detected DEspR+ TVECs, TCs, and CD133+ putative CSCs in contrast to respective normal tissues. DEspR expression on TCs and TVECs were confirmed in PCa (Panc1) and GBM (U87) cell lines, and HUVECs undergoing angiogenesis, respectively. Dose-dependent anti-DEspR mAb inhibition decreased HUVEC angiogenesis and Panc1 invasiveness compared to isotype controls. DEspR+ expression was detected in functionally validated Panc1 and U87 CSCs exhibiting tumorsphere formation, increased tumorigenicity in nude rat xenograft models, and self-renewal from xenograft tumors. DEspR inhibition decreased tumorsphere formation and increased dead cell numbers, suggesting decreased anoikis resistance for both U87 and Panc1 CSCs. Phosphoproteome analysis detected DEspR signaling through phosphoproteins implicated in TVEC-TC crosstalk, angiogenesis, and anoikis resistance. DEspR inhibition decreased tumor growth of Panc1 and U87 CSC-enriched subcutaneous xenograft tumors in nude rat models. Conclusions: Data demonstrate DEspR as a common target on TVECs, TCs, and CSCs in PCa and GBM, whose inhibition provides a potential therapeutic strategy for simultaneous inhibition of multiple pro-malignancy steps: angiogenesis, invasiveness, and anoikis resistance.
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Chaudhary, Prakash, Diwakar Guragain, Jae-Hoon Chang y Jung-Ae Kim. "TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma". Cancers 13, n.º 21 (22 de octubre de 2021): 5305. http://dx.doi.org/10.3390/cancers13215305.
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In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT7, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT7. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by downregulation of TPH1 and 5-HT7. Co-immunoprecipation with EZH2 and pan-methyl lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. Furthermore, the inhibitor of EZH2, TPH1, or 5-HT7 effectively regressed pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical action of EZH2 allowed the expression of TPH1-5-HT7 axis leading to gemcitabine resistance and CSC population in PDAC.
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Luo, Zhaofan, Yanan Li, Mingxin Zuo, Chang Liu, Dong Yan, Huamin Wang y Donghui Li. "Effect of NR5A2 inhibition on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers". Molecular Carcinogenesis 56, n.º 5 (12 de enero de 2017): 1438–48. http://dx.doi.org/10.1002/mc.22604.
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Mortoglou, Maria, Francesc Miralles, Elif Damla Arisan, Alwyn Dart, Stipo Jurcevic, Sigrun Lange y Pinar Uysal-Onganer. "microRNA-21 Regulates Stemness in Pancreatic Ductal Adenocarcinoma Cells". International Journal of Molecular Sciences 23, n.º 3 (24 de enero de 2022): 1275. http://dx.doi.org/10.3390/ijms23031275.
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Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer (PCa) with a low survival rate. microRNAs (miRs) are endogenous, non-coding RNAs that moderate numerous biological processes. miRs have been associated with the chemoresistance and metastasis of PDAC and the presence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs). In this study, we investigated the role of miR-21, which is highly expressed in Panc-1 and MiaPaCa-2 PDAC cells in association with CSCs. Following miR-21 knockouts (KO) from both MiaPaCa-2 and Panc-1 cell lines, reversed expressions of epithelial–mesenchymal transition (EMT) and CSCs markers were observed. The expression patterns of key CSC markers, including CD44, CD133, CX-C chemokine receptor type 4 (CXCR4), and aldehyde dehydrogenase-1 (ALDH1), were changed depending on miR-21 status. miR-21 (KO) suppressed cellular invasion of Panc-1 and MiaPaCa-2 cells, as well as the cellular proliferation of MiaPaCa-2 cells. Our data suggest that miR-21 is involved in the stemness of PDAC cells, may play roles in mesenchymal transition, and that miR-21 poses as a novel, functional biomarker for PDAC aggressiveness.
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Pook, Hannah y Siim Pauklin. "Mechanisms of Cancer Cell Death: Therapeutic Implications for Pancreatic Ductal Adenocarcinoma". Cancers 13, n.º 19 (28 de septiembre de 2021): 4834. http://dx.doi.org/10.3390/cancers13194834.
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Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer that is strongly associated with poor prognosis and short median survival times. In stark contrast to the progress seen in other cancer types in recent decades, discoveries of new treatments in PDAC have been few and far between and there has been little improvement in overall survival (OS). The difficulty in treating this disease is multifactorial, contributed to by late presentation, difficult access to primary tumour sites, an ‘immunologically cold’ phenotype, and a strong tendency of recurrence likely driven by cancer stem cell (CSC) populations. Furthermore, apparently contrasting roles of tumour components (such as fibrotic stroma) and intracellular pathways (such as autophagy and TGFβ) have made it difficult to distinguish beneficial from detrimental drug targets. Despite this, progress has been made in the field, including the determination of mFOLFIRINOX as the standard-of-care adjuvant therapy and the discovery of KRASG12C mutant inhibitors. Moreover, new research, as outlined in this review, has highlighted promising new approaches including the targeting of the tumour microenvironment, enhancement of immunotherapies, epigenetic modulation, and destruction of CSCs.
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Li, Jian, Yunchao Wang, Jiayun Ge, Wenhua Li, Liangyu Yin, Zhiping Zhao, Songsong Liu et al. "Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer". Cellular Physiology and Biochemistry 51, n.º 1 (2018): 262–77. http://dx.doi.org/10.1159/000495228.
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Background/Aims: Cancer stem cells (CSCs) are largely responsible for tumor relapse and metastatic behavior. Doublecortin-like kinase 1 (DCLK1) was recently reported to be a biomarker for gastrointestinal CSCs and involved in the epithelial-mesenchymal transition (EMT) and tumor progression. B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) is a crucial regulator of CSC self-renewal, malignant transformation and EMT, and a previous study from our group showed that Bmi-1 is upregulated in pancreatic cancer progression and participates in EMT. However, it remains unclear whether DCLK1 is involved in pancreatic cancer or whether DCLK1 is associated with the altered level of Bmi-1 expression. Methods: The correlation of DCLK1 expression and clinical features of pancreatic cancer was analyzed in 210 paraffin-embedded archived pancreatic cancer specimens by immunohistochemical analysis. The biological effects of DCLK1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays, cell migration by wound healing assay and cell invasion by Transwell invasion assay. We further investigated the effect of therapeutic siRNA targeting DCLK1 on pancreatic cancer cell growth in vivo. Moreover, the molecular mechanism by which DCLK1 upregulates Bmi-1 expression was explored using real-time PCR, western blotting and Co-immunoprecipitation assay. Results: DCLK1 is overexpressed in pancreatic cancer and is related to metastasis and prognosis. Knockdown of DCLK1 markedly suppressed cell growth in vitro and in vivo and also inhibited the migration and invasion of pancreatic cancer cells. Furthermore, we found that DCLK1 silencing could inhibit EMT in cancer cells via downregulation of Bmi-1 and the mesenchymal markers Snail and Vimentin and upregulation of the epithelial marker E-cadherin. Moreover, high DCLK1 expression in human pancreatic cancer samples was associated with a mesenchymal phenotype and increased cell proliferation. Further co-immunoprecipitation indicated that DCLK1 did not interact with Bmi-1 directly. Conclusion: Our data suggest that upregulation of DCLK1 may contribute to pancreatic cancer metastasis and poor prognosis by increasing Bmi-1 expression indirectly. The findings indicate that inhibiting DCLK1 expression might be a novel strategy for pancreatic cancer therapy.
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Tsai, Kelvin K., Tze-Sian Chan y Yuval Shaked. "Next Viable Routes to Targeting Pancreatic Cancer Stemness: Learning from Clinical Setbacks". Journal of Clinical Medicine 8, n.º 5 (17 de mayo de 2019): 702. http://dx.doi.org/10.3390/jcm8050702.
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Pancreatic ductal adenocarcinoma (PDAC) is a devastating and highly aggressive malignancy. Existing therapeutic strategies only provide a small survival benefit in patients with PDAC. Laboratory and clinical research have identified various populations of stem-cell-like cancer cells or cancer stem cells (CSCs) as the driving force of PDAC progression, treatment-resistance, and metastasis. Whilst a number of therapeutics aiming at inhibiting or killing CSCs have been developed over the past decade, a series of notable clinical trial setbacks have led to their deprioritization from the pipelines, triggering efforts to refine the current CSC model and exploit alternative therapeutic strategies. This review describes the current and the evolving models of pancreatic CSCs (panCSCs) and the potential factors that hamper the clinical development of panCSC-targeted therapies, emphasizing the heterogeneity, the plasticity, and the non-binary pattern of cancer stemness, as well as the desmoplastic stroma impeding drug penetration. We summarized novel and promising therapeutic strategies implicated by the works of our groups and others’ that may overcome these hurdles and have shown efficacies in preclinical models of PDAC, emphasizing the unique advantages of targeting the stroma-engendered panCSC-niches and metronomic chemotherapy. Finally, we proposed feasible clinical trial strategies and biomarkers that can guide the next-generation clinical trials.
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Azmi, Asfar S., William Senapedis, Erkan Baloglu, Yosef Landesman, Ori Kalid, Amro Aboukameel, Bin Bao et al. "Novel PAK4 inhibitors for pancreatic cancer therapy." Journal of Clinical Oncology 32, n.º 3_suppl (20 de enero de 2014): 233. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.233.
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233 Background: Pancreatic cancer (PC) is a deadly disease in urgent need of novel molecularly targeted drugs. Gene copy number amplification studies in PC patient cohorts has shown amplification of the p21-activated kinase (PAK) family member PAK4. PAK4 acts as a key effector of the Rho family GTPases downstream of Ras signaling. Moreover, PAK4 protein is over-expressed in PC cell lines but not in normal human pancreatic ductal epithelial (HPDE) cells. Most importantly, RNA interference of PAK4 has been shown to suppress PC cell proliferation. These studies clearly make PAK4 an attractive therapeutic target especially because direct targeting of Kras has been a failure. Methods: We have identified a new class of PAK4 allosteric modulators that show anti-proliferative activity against several PC cell lines (IC50s <250nM) while sparing normal HPDE (IC50s5 fold higher). Results: Cell growth inhibition is concurrent with apoptosis induction and suppression of colony formation in the PC cell lines (and not in HPDE cells). Our small molecule PAK4 allosteric modulator, KPT-7189, suppresses PAK4 protein expression and caused reversal of anti-apoptotic signaling. PAK4 RNA interference enhances KPT-7189 activity, and co-immunoprecipitation experiments showed disruption of PAK4 binding partners. KPT-7189 also inhibited spheroid forming ability of highly resistant PC cells carrying markers of cancer stem cells (CSCs;triple positive for CD33+CD44+EpCAM+) consistent with epithelial-to-mesenchymal (EMT) phenotype. Molecular analyses of KPT-7189 treated CD33+CD44+EpCAM+ spheroids showed suppression of EMT and CSC markers with re-expression of epithelial phenotype markers. Another potent PAK allosteric modulator in the same series, KPT-7651 showing good oral bioavailability (%F = 95%) was well tolerated by mice with a maximum tolerated dose of 60 mg/kg following oral administration. Pre-clinical animal efficacy trial in sub-cutaneous, orthotopic and LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre transgenic mice model is currently under investigation. Conclusions: This is the first proof of concept study demonstrating the development of a PAK4-targeted drug for the treatment of PC, and thus further pre-clinical and clinical investigations are warranted.