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1
Grassi, Elisa Stellaria, Viola Ghiandai, and Luca Persani. "Thyroid Cancer Stem-Like Cells: From Microenvironmental Niches to Therapeutic Strategies." Journal of Clinical Medicine 10, no. 7 (April 1, 2021): 1455. http://dx.doi.org/10.3390/jcm10071455.
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Thyroid cancer (TC) is the most common endocrine malignancy. Recent progress in thyroid cancer biology revealed a certain degree of intratumoral heterogeneity, highlighting the coexistence of cellular subpopulations with distinct proliferative capacities and differentiation abilities. Among those subpopulations, cancer stem-like cells (CSCs) are hypothesized to drive TC heterogeneity, contributing to its metastatic potential and therapy resistance. CSCs principally exist in tumor areas with specific microenvironmental conditions, the so-called stem cell niches. In particular, in thyroid cancer, CSCs’ survival is enhanced in the hypoxic niche, the immune niche, and some areas with specific extracellular matrix composition. In this review, we summarize the current knowledge about thyroid CSCs, the tumoral niches that allow their survival, and the implications for TC therapy.
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Shah, Sumedh, Garima Yagnik, Alan Nguyen, Harsh Wadhwa, Jordan Spatz, Michael Safaee, Justin Cheng, and Manish Aghi. "TMIC-57. PRO-TUMORAL EFFECTS OF INTRA-TUMORAL NEUTROPHILS IN THE GLIOBLASTOMA MICROENVIRONMENT." Neuro-Oncology 21, Supplement_6 (November 2019): vi260. http://dx.doi.org/10.1093/neuonc/noz175.1091.
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Abstract While macrophage enrichment and lymphocyte depletion have been described in glioblastoma, intratumoral neutrophils and their effect on glioblastoma have been under-characterized. While tumor-associated neutrophils (TANs) were initially regarded as passive bystanders due to their short-lived nature, investigation of TANs in other cancer types revealed pro-tumoral roles. Therefore, we sought to characterize TANs in the glioblastoma microenvironment using transcriptomic analysis and define their oncologic effects. Flow cytometric analysis of patient samples for neutrophils (CD11b+/CD15+/CD66b+) revealed higher percentages of TANs in glioblastoma compared to low-grade gliomas (1.76% [n=13] vs. 0.33% [n=6], p=0.03). Using the Transwell migration assay with glioblastoma tumor conditioned-media (CM), we found that recruitment of circulating neutrophils to tumor sites is mediated by leukotriene-B4 chemoattraction and that this interaction can be blocked with the addition of LtB4 receptor antagonist, LY293111. TANs were morphologically activated, unlike circulating neutrophils from GBM patients (P< 0.05) and, while not intravascular, were close to blood vessels. We performed single-cell RNA sequencing of isolated TANs and found a distinct transcriptomic profile relative to circulating neutrophils from these patients, particularly upregulated osteopontin. Osteopontin concentration was significantly higher in TAN CM than in patient-matched peripheral blood neutrophil CM (3.2ng/mL [n=3] vs. 0.02ng/mL [n=3], p< 0.05). Because osteopontin is linked to GBM stem cell-like phenotype maintenance and TANs localized to the perivascular niche where GBM stem cells reside, we investigated TAN-GBM stem cell interactions and osteopontin as a potential mediator. We found TAN CM increased proliferation and stem cell markers (Nanog, Oct4, Sox2) of stem cell-containing GBM neurospheres (p< 0.01). These effects were blocked by osteopontin-neutralizing antibodies (p< 0.01). Our work defines neutrophil-mediated pro-tumoral effects and their mechanisms and identifies a novel approach to target GBM stem cells—by disrupting the immune cell mediators that create their supportive microenvironment in the perivascular niche.
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Jandial, Rahul, and Khairul I Ansari. "Peri-tumoral neural niche in brain metastasis from breast cancer." Integrative Cancer Science and Therapeutics 3, no. 4 (2016): 509. http://dx.doi.org/10.15761/icst.1000199.
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Stöth, Manuel, Aida Freire Valls, Mingyi Chen, Sarah Hidding, Karl Knipper, Ying Shen, Johannes Klose, et al. "Splenectomy reduces lung metastases and tumoral and metastatic niche inflammation." International Journal of Cancer 145, no. 9 (November 2019): 2509–20. http://dx.doi.org/10.1002/ijc.32378.
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Chung, Hyewon, Sang Wha Kim, and Seung Hyeok Seok. "Abstract B009: Tumoral activation of endothelium drives macrophages-mediated metastatic niche formation and promotes lung metastasis." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): B009. http://dx.doi.org/10.1158/1538-7445.metastasis22-b009.
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Abstract Primary tumor induces macrophages-enriched environment to establish metastatic niche which enhances homing and colonization of circulating tumor cells. However, the molecular mechanism underlying endothelial remodeling that favors macrophages infiltration and subsequent niche formation is not fully understood. Here, we found that tumor-derived factors activated endothelial cells to increase adhesive efficacy of monocytes to the endothelium, leading to macrophage infiltration. In mouse models of pulmonary metastasis, this endothelial activation triggered formation of premetastatic niche via accumulation of macrophages in the lungs. Of note, macrophages primed the metastatic microenvironment through enhancing expression of niche-related genes including S100A8, S100A9, MMP9 and fibronectin within the premetastatic lungs and directly transmitted survival signal to tumor cells in a contact-dependent manner. Furthermore, we demonstrated that depletion of macrophages specifically during premetastatic stages reduced niche formation and also resulted in reduced metastatic burden. These findings suggest that endothelial remodeling at metastatic site is a key step for initiation of premetastatic niche formation supported by macrophages. Targeting this step could present an opportunity for therapeutic intervention of metastatic spread in patients with malignant cancers. Citation Format: Hyewon Chung, Sang Wha Kim, Seung Hyeok Seok. Tumoral activation of endothelium drives macrophages-mediated metastatic niche formation and promotes lung metastasis [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 B009.
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Garcia-Mazas, Carla, Noemi Csaba, and Marcos Garcia-Fuentes. "Biomaterials to suppress cancer stem cells and disrupt their tumoral niche." International Journal of Pharmaceutics 523, no. 2 (May 2017): 490–505. http://dx.doi.org/10.1016/j.ijpharm.2016.12.013.
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Jansen, Caroline S., Nataliya Prokhnevska, Viraj A. Master, Martin G. Sanda, Jennifer W. Carlisle, Mehmet Asim Bilen, Maria Cardenas, et al. "An intra-tumoral niche maintains and differentiates stem-like CD8 T cells." Nature 576, no. 7787 (December 11, 2019): 465–70. http://dx.doi.org/10.1038/s41586-019-1836-5.
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Moffet, Joel, Oluwaseun Fatunla, James Whittle, Jones Jordan, Samuel Roberts-Thomson, Anna Pavenko, David Scoville, et al. "TMIC-36. SPATIAL ARCHITECTURE OF HIGH-GRADE GLIOMA REVEALS TUMOR HETEROGENEITY WITHIN DISTINCT DOMAINS." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v286. http://dx.doi.org/10.1093/neuonc/noad179.1102.
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Abstract High-grade gliomas are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Recently, spatial technologies have emerged to dissect this complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. Here, we construct a high-resolution molecular landscape of GBM and IDH-mutant high-grade glioma patient samples to investigate the cellular subtypes and spatial communities that compose high-grade glioma using digital spatial profiling and spatial molecular imaging. This uncovered striking diversity of the tumor and immune microenvironment, that is embodied by the heterogeneity of the inferred copy-number alterations in the tumor. Reconstructing the tumor architecture revealed two distinct niches, one composed of tumor cell states that most closely resemble normal glial cells, associated with microglia; and the other niche populated by monocytes and mesenchymal tumor cells. We further reveal that communication between tumor and immune cells is underpinned by tumor-specific ligands, such as TGFb signaling in astrocyte-like tumor cells. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localized regions.
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Infanger, David W., YouJin Cho, Brina S. Lopez, Sunish Mohanan, S. Chris Liu, Demirkan Gursel, John A. Boockvar, and Claudia Fischbach. "Glioblastoma Stem Cells Are Regulated by Interleukin-8 Signaling in a Tumoral Perivascular Niche." Cancer Research 73, no. 23 (October 11, 2013): 7079–89. http://dx.doi.org/10.1158/0008-5472.can-13-1355.
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Xiang, Lisha, and Daniele Gilkes. "The Contribution of the Immune System in Bone Metastasis Pathogenesis." International Journal of Molecular Sciences 20, no. 4 (February 25, 2019): 999. http://dx.doi.org/10.3390/ijms20040999.
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Bone metastasis is associated with significant morbidity for cancer patients and results in a reduced quality of life. The bone marrow is a fertile soil containing a complex composition of immune cells that may actually provide an immune-privileged niche for disseminated tumor cells to colonize and proliferate. In this unique immune milieu, multiple immune cells including T cells, natural killer cells, macrophages, dendritic cells, myeloid-derived suppressor cells, and neutrophils are involved in the process of bone metastasis. In this review, we will discuss the crosstalk between immune cells in bone microenvironment and their involvement with cancer cell metastasis to the bone. Furthermore, we will highlight the anti-tumoral and pro-tumoral function of each immune cell type that contributes to bone metastasis. We will end with a discussion of current therapeutic strategies aimed at sensitizing immune cells.
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Quiroz-Reyes, Adriana G., Jose F. Islas, Paulina Delgado-Gonzalez, Hector Franco-Villarreal, and Elsa N. Garza-Treviño. "Therapeutic Approaches for Metastases from Colorectal Cancer and Pancreatic Ductal Carcinoma." Pharmaceutics 13, no. 1 (January 14, 2021): 103. http://dx.doi.org/10.3390/pharmaceutics13010103.
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Metastasis is the process of dissemination of a tumor, whereby cells from the primary site dislodge and find their way to other tissues where secondary tumors establish. Metastasis is the primary cause of death related to cancer. This process warrants changes in original tumoral cells and their microenvironment to establish a metastatic niche. Traditionally, cancer therapy has focused on metastasis prevention by systematic treatments or direct surgical re-sectioning. However, metastasis can still occur. More recently, new therapies direct their attention to targeting cancer stem cells. As they propose, these cells could be the orchestrators of the metastatic niche. In this review, we describe conventional and novel developments in cancer therapeutics for liver and lung metastasis. We further discuss the resistance mechanisms of targeted therapy, the advantages, and disadvantages of diverse treatment approaches, and future novel strategies to enhance cancer prognosis.
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Beniwal, Angad, Saket Jain, Sumedh Shah, Sabraj Gill, Garima Yagnik, Alan Nguyen, Harsh Wadhwa, Aaron Diaz, and Manish K. Aghi. "TAMI-38. TUMOR-ASSOCIATED NEUTROPHILS IN GLIOBLASTOMA PROMOTE THE PERIVASCULAR GLIOMA STEM-LIKE CELL NICHE VIA OSTEOPONTIN SECRETION." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi206. http://dx.doi.org/10.1093/neuonc/noab196.822.
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Abstract Among clinical analyses, elevated neutrophil-lymphocyte ratio has been correlated with poor outcomes of glioblastoma patients independent of other prognostic factors. Additionally, our flow cytometric studies of primary patient samples found neutrophil percentage to be significantly higher in higher-grade glioma versus lower-grade glioma. Tumor-associated neutrophils (TANs) comprise less than 2% of the glioblastoma microenvironment. While TANs were initially considered passive bystanders due to their short-lived nature, investigation of TANs in other cancers revealed distinct pro-tumoral roles. Therefore, we transcriptomically characterized glioblastoma TANs and defined their oncologic effects. Transcriptomic analysis of patient-matched TANs versus peripheral blood neutrophils revealed that functionally quiescent circulating neutrophils infiltrate IDH1-wild type glioblastoma via leukotriene B4 chemoattraction, where tumor cells morphologically and transcriptomically activate them to become TANs. Single-cell RNA-sequencing of patient-matched TANs and peripheral blood neutrophils revealed a subset of tumor-activated neutrophils which adopt a pro-tumoral secretory phenotype, marked by activation of the IL-17 signaling pathway and high osteopontin production. Using immunofluorescence stains of primary patient glioblastoma sections, we demonstrated that activated, myeloperoxidase-positive TANs reside in the perivascular niche of glioblastoma in close proximity to glioblastoma stem-like cells (GSCs) and CD31-positive endothelial cells. Further analysis in culture demonstrated that TAN-secreted osteopontin drives the formation, self-renewal, and proliferation of GSC-containing neurospheres. These results were validated using a syngeneic stem cell-derived IDH1-wild type murine glioblastoma model in vivo. Thus, while TANs are rare in glioblastoma, their enrichment in the glioblastoma perivascular niche uniquely positions them to support the GSCs that are crucial to therapeutic resistance of GBM.
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Mendoza-Reinoso, Veronica, Laurie K. McCauley, and Pierrick G. J. Fournier. "Contribution of Macrophages and T Cells in Skeletal Metastasis." Cancers 12, no. 4 (April 20, 2020): 1014. http://dx.doi.org/10.3390/cancers12041014.
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Bone is a common site for metastases with a local microenvironment that is highly conducive for tumor establishment and growth. The bone marrow is replete with myeloid and lymphoid linage cells that provide a fertile niche for metastatic cancer cells promoting their survival and growth. Here, we discuss the role of macrophages and T cells in pro- and anti-tumoral mechanisms, their interaction to support cancer cell growth, and their contribution to the development of skeletal metastases. Importantly, immunotherapeutic strategies targeting macrophages and T cells in cancer are also discussed in this review as they represent a great promise for patients suffering from incurable bone metastases.
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Ghiabi, Pegah, Jie Jiang, Jennifer Pasquier, Mahtab Maleki, Nadine Abu-Kaoud, Najeeb Halabi, Bella S. Guerrouahen, Shahin Rafii, and Arash Rafii. "Breast cancer cells promote a notch-dependent mesenchymal phenotype in endothelial cells participating to a pro-tumoral niche." Journal of Translational Medicine 13, no. 1 (2015): 27. http://dx.doi.org/10.1186/s12967-015-0386-3.
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Xu, Xiaowen, Wenjun Chang, Jie Yuan, Xue Han, Xiaojie Tan, Yibo Ding, Yanxin Luo, et al. "Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinomaviacreating a cancer-supportive niche." Oncotarget 7, no. 1 (November 9, 2015): 798–813. http://dx.doi.org/10.18632/oncotarget.5985.
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Belgiovine, Cristina, Elisabeth Digifico, Clément Anfray, Aldo Ummarino, and Fernando Torres Andón. "Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing." Journal of Clinical Medicine 9, no. 10 (October 8, 2020): 3226. http://dx.doi.org/10.3390/jcm9103226.
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In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.
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Paolillo, Mayra, Sergio Comincini, and Sergio Schinelli. "In Vitro Glioblastoma Models: A Journey into the Third Dimension." Cancers 13, no. 10 (May 18, 2021): 2449. http://dx.doi.org/10.3390/cancers13102449.
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Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with an average survival time of about one year from initial diagnosis. In the attempt to overcome the complexity and drawbacks associated with in vivo GBM models, together with the need of developing systems dedicated to screen new potential drugs, considerable efforts have been devoted to the implementation of reliable and affordable in vitro GBM models. Recent findings on GBM molecular features, revealing a high heterogeneity between GBM cells and also between other non-tumor cells belonging to the tumoral niche, have stressed the limitations of the classical 2D cell culture systems. Recently, several novel and innovative 3D cell cultures models for GBM have been proposed and implemented. In this review, we first describe the different populations and their functional role of GBM and niche non-tumor cells that could be used in 3D models. An overview of the current available 3D in vitro systems for modeling GBM, together with their major weaknesses and strengths, is presented. Lastly, we discuss the impact of groundbreaking technologies, such as bioprinting and multi-omics single cell analysis, on the future implementation of 3D in vitro GBM models.
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Conigliaro, Alice, and Carla Cicchini. "Exosome-Mediated Signaling in Epithelial to Mesenchymal Transition and Tumor Progression." Journal of Clinical Medicine 8, no. 1 (December 27, 2018): 26. http://dx.doi.org/10.3390/jcm8010026.
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Growing evidence points to exosomes as key mediators of cell–cell communication, by transferring their specific cargo (e.g., proteins, lipids, DNA and RNA molecules) from producing to receiving cells. In cancer, the regulation of the exosome-mediated intercellular communication may be reshaped, inducing relevant changes in gene expression of recipient cells in addition to microenvironment alterations. Notably, exosomes may deliver signals able to induce the transdifferentiation process known as Epithelial-to-Mesenchymal Transition (EMT). In this review, we summarize recent findings on the role of exosomes in tumor progression and EMT, highlighting current knowledge on exosome-mediated intercellular communication in tumor-niche establishment, migration, invasion, and metastasis processes. This body of evidence suggests the relevance of taking into account exosome-mediated signaling and its multifaceted aspects to develop innovative anti-tumoral therapeutic approaches.
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Ghiabi, Pegah, Jie Jiang, Jennifer Pasquier, Mahtab Maleki, Nadine Abu-Kaoud, Shahin Rafii, and Arash Rafii. "Endothelial Cells Provide a Notch-Dependent Pro-Tumoral Niche for Enhancing Breast Cancer Survival, Stemness and Pro-Metastatic Properties." PLoS ONE 9, no. 11 (November 7, 2014): e112424. http://dx.doi.org/10.1371/journal.pone.0112424.
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Bartlett, Alexandra Q., Nathan D. Pennock, Alex Klug, and Pepper Schedin. "Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis." Cancers 13, no. 7 (April 3, 2021): 1698. http://dx.doi.org/10.3390/cancers13071698.
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In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.
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Uribe, Daniel, Ignacio Niechi, Gorjana Rackov, José I. Erices, Rody San Martín, and Claudia Quezada. "Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity." Biology 11, no. 2 (February 16, 2022): 313. http://dx.doi.org/10.3390/biology11020313.
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Glioblastoma (GBM) is the most frequent and aggressive brain tumor, characterized by great resistance to treatments, as well as inter- and intra-tumoral heterogeneity. GBM exhibits infiltration, vascularization and hypoxia-associated necrosis, characteristics that shape a unique microenvironment in which diverse cell types are integrated. A subpopulation of cells denominated GBM stem-like cells (GSCs) exhibits multipotency and self-renewal capacity. GSCs are considered the conductors of tumor progression due to their high tumorigenic capacity, enhanced proliferation, invasion and therapeutic resistance compared to non-GSCs cells. GSCs have been classified into two molecular subtypes: proneural and mesenchymal, the latter showing a more aggressive phenotype. Tumor microenvironment and therapy can induce a proneural-to-mesenchymal transition, as a mechanism of adaptation and resistance to treatments. In addition, GSCs can transition between quiescent and proliferative substates, allowing them to persist in different niches and adapt to different stages of tumor progression. Three niches have been described for GSCs: hypoxic/necrotic, invasive and perivascular, enhancing metabolic changes and cellular interactions shaping GSCs phenotype through metabolic changes and cellular interactions that favor their stemness. The phenotypic flexibility of GSCs to adapt to each niche is modulated by dynamic epigenetic modifications. Methylases, demethylases and histone deacetylase are deregulated in GSCs, allowing them to unlock transcriptional programs that are necessary for cell survival and plasticity. In this review, we described the effects of GSCs plasticity on GBM progression, discussing the role of GSCs niches on modulating their phenotype. Finally, we described epigenetic alterations in GSCs that are important for stemness, cell fate and therapeutic resistance.
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Nambiar, Dhanya K., Vignesh Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, et al. "Abstract 66: Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment." Cancer Research 83, no. 7_Supplement (April 4, 2023): 66. http://dx.doi.org/10.1158/1538-7445.am2023-66.
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Abstract Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (Gal1) is a known modulator of tumor growth and progression in multiple cancer types including head and neck cancer (HNC). However, its contribution to the regulation of metastasis is poorly understood. Through this study we report a previously unknown role for Gal1 in modulating the STING pathway to regulate metastasis. The cGAS-STING pathway has paradoxical roles in cancer depending on the kinetics and strength of its induction, with chronic STING activation being linked to immune suppression and tumor progression while acute activation being associated with immune activation. However, little is known about the pathways that promote chronic STING activation. Using HNC and lung cancer models, we show that Gal-1 enhances STING protein stability, leading to sustained NF-κΒ activation and heightened chemokine-driven recruitment of myeloid derived suppressor cells (MDSCs). We show that Gal1-STING connection fosters the establishment of pre-metastatic niche through polymorphonuclear MDSCs (PMN-MDSCs), which modify the local lung microenvironment to support metastatic spread. Notably, RNA sequencing of MDSCs isolated from pre-metastatic lungs indicate the role of PMN-MDSCs in remodeling collagen and the extracellular matrix in the pre-metastatic compartment. Our findings reveal an unexpected role of STING activation in metastatic progression of HNC and lung cancer models and establish Gal1 as an endogenous positive regulator of STING. Citation Format: Dhanya K. Nambiar, Vignesh Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Koong, Rie Eyben, Amato Giaccia, Lingyin Li, Edgar Engleman, Quynh Thu Le. Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 66.
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Rick, Jonathan, Alan Nguyen, Ankush Chandra, Harsh Wadhwa, Sumedh Shah, Lin Wang, Darryl Lau, et al. "TMIC-22. IDENTIFICATION OF CANCER-ASSOCIATED FIBROBLASTS IN GLIOBLASTOMA and Defining Their Protumoral Effects." Neuro-Oncology 21, Supplement_6 (November 2019): vi252. http://dx.doi.org/10.1093/neuonc/noz175.1056.
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Abstract While cancer-associated fibroblasts (CAFs) and their pro-tumoral effects have been demonstrated in systemic cancers, CAFs had been presumed absent in glioblastoma given the lack of normal fibroblasts in the healthy brain. Here, we show that 5–26% (mean=12%) of cells in human glioblastomas express CAF markers α-SMA or PDGFR-β, morphologically resemble fibroblasts, and transcriptomically resemble by RNA-seq CAFs from other cancers. Glioblastoma CAFs were chemotactically attracted to glioblastoma-initiating stem cells (P=0.02). While glioblastoma CAFs did not affect differentiated glioblastoma cell proliferation (P=0.4), CAFs increased glioblastoma stem cell proliferation (P=0.002) and expression of glioblastoma stem cell-associated genes (P< 0.001). To identify mediators of CAF/glioblastoma stem cell interactions, we created a resource of inferred crosstalk by mapping the expression of receptors to that of their cognate ligands/agonists, using our RNA-seq results from glioblastoma CAFs and stem cells, revealing PDGF-β/PDGFR and osteopontin/CD44 to mediate stem cell recruitment of CAFs and CAF enrichment of stem cells, as confirmed by blocking antibodies (P=0.02–0.03). CAFs also render the glioblastoma microenvironment more pro-tumoral by promoting M2 polarization of tumor-associated macrophages (P=0.01), an effect we found to arise from unique CAF production of the EDA splice variant of fibronectin binding toll-like receptor 4 (TLR4), a known EDA receptor expressed by macrophages (P=0.02). In patient glioblastomas, CAFs were enriched 3-fold in the subventricular zone (SVZ) (P=0.04) which houses the neural stem cells that generate glioblastoma stem cells. SVZs from epilepsy cases or autopsies of glioblastoma-containing brains without ventricular involvement lacked CAFs. Depleting CAFs in xenografts derived from neurosphere-containing glioblastoma stem cells slowed their growth in vivo (P< 0.001). These findings are among the first to identify and profile glioblastoma CAFs. CAF recruitment by glioblastoma stem cells and creation of a pro-tumoral microenvironment in the perivascular niche housing glioblastoma stem cells, particularly in the SVZ, makes them an intriguing therapeutic target.
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Solé, Carla, and Charles Henderson Lawrie. "MicroRNAs in Metastasis and the Tumour Microenvironment." International Journal of Molecular Sciences 22, no. 9 (May 4, 2021): 4859. http://dx.doi.org/10.3390/ijms22094859.
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Metastasis is the process whereby cancer cells migrate from the primary tumour site to colonise the surrounding or distant tissue or organ. Metastasis is the primary cause of cancer-related mortality and approximately half of all cancer patients present at diagnosis with some form of metastasis. Consequently, there is a clear need to better understand metastasis in order to develop new tools to combat this process. MicroRNAs (miRNAs) regulate gene expression and play an important role in cancer development and progression including in the metastatic process. Particularly important are the roles that miRNAs play in the interaction between tumour cells and non-tumoral cells of the tumour microenvironment (TME), a process mediated largely by circulating miRNAs contained primarily in extracellular vesicles (EVs). In this review, we outline the accumulating evidence for the importance of miRNAs in the communication between tumour cells and the cells of the TME in the context of the pre-metastatic and metastatic niche.
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Everts, Anne, Melissa Bergeman, Grant McFadden, and Vera Kemp. "Simultaneous Tumor and Stroma Targeting by Oncolytic Viruses." Biomedicines 8, no. 11 (November 5, 2020): 474. http://dx.doi.org/10.3390/biomedicines8110474.
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Current cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts, the (compact) extracellular matrix, tumor vasculature, and tumor-associated macrophages, which all exert crucial roles in maintaining a pro-tumoral niche. Their continuous complex interactions with tumor cells promote tumor progression and metastasis, emphasizing the challenges in tumor therapy development. Over the last decade, advances in oncolytic virotherapy have shown that oncolytic viruses (OVs) are a promising multi-faceted therapeutic platform for simultaneous tumor and stroma targeting. In addition to promoting tumor cell oncolysis and systemic anti-tumor immunity, accumulating data suggest that OVs can also directly target stromal components, facilitating OV replication and spread, as well as promoting anti-tumor activity. This review provides a comprehensive overview of the interactions between native and genetically modified OVs and the different targetable tumor stromal components, and outlines strategies to improve stroma targeting by OVs.
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Belhabib, Ismahane, Sonia Zaghdoudi, Claire Lac, Corinne Bousquet, and Christine Jean. "Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?" Cancers 13, no. 14 (July 11, 2021): 3466. http://dx.doi.org/10.3390/cancers13143466.
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Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of the key, complex and multiple roles of the ECM in cancer and of the CAF diversity, has revolutionized the field and raised innovative but challenging questions. Here, we rapidly present CAF heterogeneity in link with their specific ECM remodeling features observed in cancer, before developing each of the impacts of such ECM modifications on tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc.), and on patient prognosis. Finally, based on preclinical studies and recent results obtained from clinical trials, we highlight key mechanisms or proteins that are, or may be, used as potential therapeutic or diagnostic targets, and we report and discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies.
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Cosentino, Giulia, Sandra Romero-Cordoba, Ilaria Plantamura, Alessandra Cataldo, and Marilena V. Iorio. "miR-9-Mediated Inhibition of EFEMP1 Contributes to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts." Cells 9, no. 9 (September 22, 2020): 2143. http://dx.doi.org/10.3390/cells9092143.
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Tumor growth and invasion occurs through a dynamic interaction between cancer and stromal cells, which support an aggressive niche. MicroRNAs are thought to act as tumor messengers to “corrupt” stromal cells. We previously demonstrated that miR-9, a known metastamiR, is released by triple negative breast cancer (TNBC) cells to enhance the transition of normal fibroblasts (NFs) into cancer-associated fibroblast (CAF)-like cells. EGF containing fibulin extracellular matrix protein 1 (EFEMP1), which encodes for the ECM glycoprotein fibulin-3, emerged as a miR-9 putative target upon miRNA’s exogenous upmodulation in NFs. Here we explored the impact of EFEMP1 downmodulation on fibroblast’s acquisition of CAF-like features, and how this phenotype influences neoplastic cells to gain chemoresistance. Indeed, upon miR-9 overexpression in NFs, EFEMP1 resulted downmodulated, both at RNA and protein levels. The luciferase reporter assay showed that miR-9 directly targets EFEMP1 and its silencing recapitulates miR-9-induced pro-tumoral phenotype in fibroblasts. In particular, EFEMP1 siRNA-transfected (si-EFEMP1) fibroblasts have an increased ability to migrate and invade. Moreover, TNBC cells conditioned with the supernatant of NFs transfected with miR-9 or si-EFEMP1 became more resistant to cisplatin. Overall, our results demonstrate that miR-9/EFEMP1 axis is crucial for the conversion of NFs to CAF-like cells under TNBC signaling.
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Ghiabi, Pegah. "Notch-Mediated Crosstalk Between Breast Cancer Cells And Endothelial Cells Induces A Transitional Endmt Phenotype Participating To An Endothelial Pro-Tumoral Niche." Qatar Foundation Annual Research Forum Proceedings, no. 2013 (November 2013): BIOSP 025. http://dx.doi.org/10.5339/qfarf.2013.biosp-025.
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Castellana, Donatello, Fatiha Zobairi, Maria Carmen Martinez, Maria Antonietta Panaro, Vincenzo Mitolo, Jean-Marie Freyssinet, and Corinne Kunzelmann. "Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis." Cancer Research 69, no. 3 (January 20, 2009): 785–93. http://dx.doi.org/10.1158/0008-5472.can-08-1946.
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Pasquier, Jennifer, Hamda Al Thawadi, Pegah Ghiabi, Nadine Abu-Kaoud, Mahtab Maleki, Bella S. Guerrouahen, Fabien Vidal, et al. "Microparticles mediated cross-talk between tumoral and endothelial cells promote the constitution of a pro-metastatic vascular niche through Arf6 up regulation." Cancer Microenvironment 7, no. 1-2 (January 15, 2014): 41–59. http://dx.doi.org/10.1007/s12307-013-0142-2.
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Zarodniuk, Maksym, Alexander Steele, Xin Lu, Jun Li, and Meenal Datta. "SDPS-30 ANALYSIS OF THE BRAIN TUMOR MATRISOME REVEALS CANCER ASSOCIATED FIBROBLASTS PREDICT POOR IMMUNOTHERAPY RESPONSE IN GLIOBLASTOMA PATIENTS." Neuro-Oncology Advances 5, Supplement_3 (August 1, 2023): iii22. http://dx.doi.org/10.1093/noajnl/vdad070.085.
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Abstract Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertook a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures. We found that glioblastoma can be divided into two ECM-based subtypes that are influenced by the presence of cells resembling cancer associated fibroblasts (CAFs) and are conserved across a number of CNS lesions. In glioblastoma, CAF-like cells are correlated with unfavorable response to immune checkpoint blockade and poor patient survival across a subset of CNS tumors. We show that CAF-like cells reside in the perivascular niche, activate chemoattractant signaling pathways to recruit tumor-associated macrophages, and promote glioma stem-like cell phenotype. Our analysis provides insights into mechanisms underlying immunotherapy resistance in glioblastoma and suggests that targeting CAF-like cells may provide an effective approach to improve patient survival in a subset of CNS tumors.
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Brisou, Gabriel, Sabrina Baaklini, Noushin Mossadegh-Keller, Alicia Beyou, Manon Zala, Laurine Gil, Camille Soun, et al. "Emergence of Highly-Plastic B Cell States Cooperates with Early Immune Microenvironment Remodeling to Drive Follicular Lymphomagenesis." Blood 142, Supplement 1 (November 28, 2023): 717. http://dx.doi.org/10.1182/blood-2023-185829.
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Follicular lymphoma (FL) is a prototypical example of B cell lymphoma arising from germinal center (GC) B cells. Recent single cell transcriptomic studies investigating the transcriptional heterogeneity of FL suggest that tumor B cells are functionally diverse with cells acquiring an intermediate phenotype between GC and memory (mem), in line with the premalignant FL ontogeny where BCL2 + memory B cells require multiple re-entries into the GC to facilitate the transformation process. Since FL cells often hijack the epigenetic machinery through mutations in histone modifying proteins - notably KMT2D - we questioned here how epigenetic alterations contribute to the emergence of this intratumoral heterogeneity. We developed a genetically engineered mouse FL-like model (GEMM) carrying Kmt2d loss-of-function in B cells and BCL2 overexpression recapitulating different progression stages from preneoplastic hyperplasia to FL-like tumors. We analyzed 45,541 high-quality single cell transcriptomes and immune repertoires (B cell receptor, BCR and T cell receptor, TCR) from 18 mice including immunized-control mice in the context of physiological GC reaction. We developed a computational workflow on mutant B cells combining supervised and unsupervised metaclustering approaches in order to highlight recurrent gene programs active in preneoplastic hyperplasia and the various stages leading to FL-like tumors. We used inferCNV to assess the association between genetics and transcriptomic heterogeneity and inferred cell-cell interactions to characterize the microenvironmental determinants associated with B cell heterogeneity throughout FL progression. By modeling the GC cycle dynamics and building B cell signatures during a normal immune response, we found that our FL GEMM mirrored the desynchronization of the GC reaction program previously observed in human FL. Single cell expression profiles of Kmt2d-BCL2 mutant cells also showed a reproducible increase in phenotypic heterogeneity during FL progression, manifesting as a continuum of cell states from proliferating GC-like to quiescent mem-like cell states. We defined this GC-to-Mem axis as the major source of intra-tumor transcriptional heterogeneity. Single-cell BCR sequencing revealed the emergence of highly-plastic B cell states during FL evolution, co-existing within individual mice and being largely independent of subclonal genetic variation. To further elucidate the emergence and maintenance of these cell state transitions, we explored the phenotypic and transcriptional changes within the immune microenvironment along disease progression. Significant compositional changes were found, including the expansion of T follicular helper cells and T regulatory T cells together with the loss of naive CD4, CD8 T, and NK cell populations, preceding malignant transformation and creating a (pre)tumoral supportive niche persisting in advanced tumors. Prior remodeling of a premalignant supportive immune niche may be crucial in establishing malignant cell heterogeneity. Ongoing efforts aim to impair tumor-immune interactions driving tumor B cell dynamics and survival. In conclusion, our results provide a high-resolution view of events spanning FL progression and indicate a major role of early TME remodeling in establishing a suitable niche for progression. Early intervention aimed to target the B cell-tumor microenvironment interactions driving intra-tumoral heterogeneity may represent a promising therapeutic avenue against early disease and prevention of FL recurrence.
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Mader, Marius, Adrian Rodrigues, Sophia Chernikova, Zheng Hao Samuel Wong, Yuelong Wang, Claudia Petritsch, Marius Wernig, and Melanie Hayden Gephart. "TMIC-85. MICROGLIA REPLACEMENT CHANGES THE TRANSCRIPTIONAL PROFILE OF TUMOR ASSOCIATED MYELOID CELLS IN MURINE MODELS OF BRAIN MALIGNANCIES." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii290. http://dx.doi.org/10.1093/neuonc/noac209.1128.
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Abstract Tumor associated microglia and macrophages (TAMs) represent a main cell type of brain malignancies and demonstrate complex interactions with cancerous cells and the tumor microenvironment. These interactions have important implications for the progression and treatment of malignant central nervous system (CNS) tumors. In a non-oncological context, it has been shown that endogenous microglia can be replaced by peripheral hematopoietic cells by genetic or pharmacological intervention. A highly efficient replacement protocol (Shibuya et al, Sci Transl Med 2022, PMID:35294256) utilizing myeloablative bone marrow transplantation (BMT) followed by microglial depletion via pharmacological inhibition of the Colony-stimulating factor-1 receptor (CSF-1R) leads to almost complete repopulation of the CNS myeloid niche by circulation-derived myeloid cells (CDMCs). We investigated if this approach could be utilized to integrate CDMCs into brain tumors and study associated changes in the TAM signature. Microglia replacement in immune-competent mice was followed by intracranial transplantation of syngeneic cell lines of either high-grade glioma (GL261) or breast cancer metastasis (E0771). Lineage tracing proved high intra- and peri-tumoral chimerism of BMT-graft derived cells among CNS myeloid cells in both models two weeks after tumor cell injection. Tumor associated CDMCs (TA-CDMCs) showed a similarly activated morphology as naïve TAMs. We used single cell RNA sequencing of CD45-positive cells to further profile the transcriptomic identity of glioma TA-CDMCs. Pathway enrichment analysis revealed an upregulation of immune response pathways in TA-CDMCs compared to regular TAMs, including the overexpression of genes relevant for the regulation of T cell activation, suggesting possible modification of the glioma immune-environment. Strategies to manipulate the myeloid niche have the potential to provide further understanding of the pathobiology of TAMs and to build the basis for novel cell therapeutic approaches in the neuro-oncological domain.
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Cittelly, Diana, Maria J. Contreras-Zarate, Karen ALvarez-Eraso, Vesna Tesic, Nicole Tsuji, Leanna Chafee, Sana Karam, D. Ryan Ormond, and Peter Kabos. "Abstract GS5-07: Estradiol represses anti-tumoral immune response to promote progression of triple-negative breast cancer brain metastases." Cancer Research 83, no. 5_Supplement (March 1, 2023): GS5–07—GS5–07. http://dx.doi.org/10.1158/1538-7445.sabcs22-gs5-07.
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Abstract Background: Younger women with breast cancer have increased risk of development of brain metastases irrespective of the tumor subtype. We have shown that pre-menopausal levels of 17-β-Estradiol (E2) contributes to the promotion of brain metastases by influencing the tumor microenvironment. E2 promotes brain metastasis (BM) of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ astrocytes in the brain niche to secrete pro-metastatic factors critical for early brain colonization. Ovarieoctomy (OVX) in combination with the aromatase inhibitor (Letrozole) prevented brain colonization of triple negative (TNBC) (ER-PR-HER2-) human xenografts (MDA231BR/NSG) and murine models (E0711/C57Bl6, 4T1/BALBc) through paracrine activation of EGFR and TRKB, pathways involved in increased invasion and early tumor initiation. Yet, the extent to which E2-depletion therapies can decrease progression of established BM in combination with current standard of care for brain metastasis remains unknown. Goal: Current standard of care (SOC) for patients with TNBC brain metastasis includes irradiation (SRS, whole brain) and immunotherapy (PD-1/PDL-1 inhibitors). The goal of this study was to assess how E2-depletion therapies affects brain immune function in the context of SOC for brain metastatic progression of TNBC. Results: To assess whether E2-depletion could decrease BM progression in a model that mimics standard of care for BM, TNBC E0771-GFP-luc cells were injected intracardially in syngeneic ovariectomized (OVX)-female C57Bl6 mice supplemented with pre-menopausal levels of E2. Seven days after injection (when cancer cells have colonized), mice received a single 15Gy dose brain irradiation and were randomized to continue receiving E2, E2 withdrawal (E2WD) or E2WD plus the aromatase-inhibitor letrozole (E2WD+LET). Brain metastatic burden significantly decreased in E2WD and E2WD+Letrozole treated mice as compared to E2-treated mice. Injection of E0711 cells in immunocompromised NSG mice or in the absence of brain irradiation abolished this effect, suggesting that E2-depletion therapies decrease BM progression through boosting radiation-induced anti-tumor immunity. Accordingly, there were no differences in BM progression in E2, E2WD or E2WD+let treated mice in a xenograft model (F2-7 TNBC cells) in NSG mice, even in the presence of brain irradiation. Immune-profiling of brains from OVX+E2, OVX and OVX+Let C57BL6 mice carrying BMs showed dynamic changes in immune populations at early and late stages of brain metastatic colonization. At early stages post brain colonization (3 days post ic injection) E2-treated mice showed a decreased fraction of CD11b+CD45Int CD206+ microglia/CNS macrophages as compared to OVX+LET-treated mice, without significant changes in the fraction of infiltrated lymphocytes, suggesting E2 represses early immunosurveillance through repression of microglia/CNS macrophage activation. At later stages of brain colonization (7 days post ic injection), E2-treated mice showed an increased fraction of proinflammatory microglia and decreased fraction of T and B cells as compared to OVX or OVX+let treated mice. While E2-depletion increased the recruitment of T cells to the brain niche, the fraction of CD279 (PD1+) brain T cells was similar among groups. Ongoing studies assess the efficacy of E2-depletion therapies in combination with brain radiation and PD-1 inhibitors to decrease metastatic burden and improve survival in preclinical models. Conclusion: Our results support the hypothesis that estradiol promotes brain metastatic progression by stimulating an immunosuppressive brain microenvironment. As such, FDA-approved E2-depletion therapies (aromatase inhibitors and selective-estrogen modulators) could be used in combination with brain irradiation and PD-1 inhibitors to promote a more effective anti-tumoral immune response. Citation Format: Diana Cittelly, Maria J. Contreras-Zarate, Karen ALvarez-Eraso, Vesna Tesic, Nicole Tsuji, Leanna Chafee, Sana Karam, D. Ryan Ormond, Peter Kabos. Estradiol represses anti-tumoral immune response to promote progression of triple-negative breast cancer brain metastases [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-07.
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Zhao, Yi, Shiva Kant, Pravin Kesarwani, Christopher Hubert, Ichiro Nakano, Joseph Fullmer, and Prakash Chinnaiyan. "MODL-02. GLIOMA ORGANOID MODEL PHENOTYPICALLY RECAPITULATES KEY ASPECTS OF MALIGNANT TRANSFORMATION IN GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii291. http://dx.doi.org/10.1093/neuonc/noac209.1130.
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Abstract Glioblastoma (GBM) displays extensive intra-tumoral heterogeneity, serving as a major obstacle for effective treatment. The identification of molecular subtypes offered promise for personalized treatment regimens in GBM, however, it has seen been determined these subtypes are reflective of intra- rather than inter-tumoral heterogeneity, with proneural (PN) and mesenchymal (MES) subtypes corresponding to the infiltrative edge and peri-necrotic core of a tumor, respectively. Further, plasticity between subtypes has been identified, with PN-to-MES transition being described as a mode of resistance. Our laboratory utilizes patient-derived, subtype-specific GBM neurospheres as a model to understand GBM heterogeneity and have previously demonstrated that these models faithfully recapitulate human disease, with PN-neurospheres expressing Olig2, having a metabolic phenotype consistent with low-grade glioma, and an indolent growth pattern in vivo when compared to aggressive, CD44 expressing MES-neurospheres. In parallel, our group demonstrated 3D-organoid models of GBM recapitulate the tumor ecology of this malignancy ex vivo. Therefore, we sought to determine if this model could be utilized to provide a window into the plasticity of GBM molecular subtypes. Consistent with their phenotype when grown as neurospheres, MES-organoids had a homogeneous distribution of proliferating cells and retained CD44 expression. In contrast, cellular heterogeneity emerged in PN organoids that could be morphologically divided into an outer, cell-dense rim and an inner core with a lower cell density. The outer rim, recapitulating a perivascular niche, contained proliferating cells, and the inner core contained necrotic cells, mimicking the hypoxic microenvironment of GBM. Intriguingly, PN organoids retained Olig2 expression in the edge, however, actively transitioned into a MES-like state in the core, expressing CD44 and metabolic reprogramming consistent with malignant transformation. Collectively, these finding support that microenvironment contributes towards PN-MES transition and PN organoid models may serve as a tool to provide a window into specific molecular and metabolic factors contributing towards transformation.
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Contreras-Zarate, Maria, Karen Alvarez-Eraso, Zachary Littrell, Nicole Tsuji, Sana Karam, D. Ryan Ormond, Peter Kabos, and Diana Cittelly. "BSCI-18 ESTROGEN-DEPLETION DECREASES PROGRESSION OF ER¯ BRAIN METASTASES BY PROMOTING AN ANTI-TUMORAL LOCAL IMMUNE RESPONSE." Neuro-Oncology Advances 4, Supplement_1 (August 1, 2022): i4. http://dx.doi.org/10.1093/noajnl/vdac078.016.
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Abstract We have shown that 17-β-Estradiol (E2) promotes brain metastasis (BM) of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ astrocytes in the brain niche to secrete pro-metastatic factors critical for early brain colonization. E2-depletion prevented brain colonization of human xenografts (MDA231BR/NSG) and syngeneic (E0711/C57Bl6, 4T1/Balb-c) ER¯ models. Yet, whether E2-depletion can be used to decrease progression of established BM and how E2-dependent modulation of brain immune response contributes to the pro-metastatic effects of E2 remains unclear. To assess whether E2-depletion could decrease BM progression in a model that mimics standard of care for BM, E0771-GFP-luc cells were injected intracardially in syngeneic ovariectomized (OVX)-female C57Bl6 mice supplemented with E2. Seven days after injection (when micrometastases are established), mice received a single 15Gy dose brain irradiation and were randomized to continue receiving E2, E2 withdrawal (E2WD) or E2WD plus the aromatase-inhibitor letrozole (EWD+LET). Endpoint BM (but not systemic metastases) were significantly decreased in E2WD+Letrozole treated mice as compared to E2-treated mice. This effect was abolished when E0711 cells were injected in severely immunocompromised NSG mice or in the absence of brain irradiation, suggesting EWD+LET decreases BM progression through boosting radiation-induced anti-tumor immunity. Accordingly, there were no differences in BM progression in E2, EWD or E2WD+let treated mice in a xenograft model (F2-7 TNBC cells) in NSG mice, even in the presence of brain irradiation. Brain immune-profiling of brain irradiated E2, EWD and EWD+Let C57BL6 mice carrying E0771 BMs shows that brains of EWD+LET-treated mice had a significantly lower fraction of CD4 T cells and an increase in CD8 T cells, suggesting that EWD+letrozole decrease brain metastatic burden in part through modulation of T cells. These results suggest E2-depletion therapies could be used in combination with brain irradiation to decrease progression of BMs and promote an anti-tumoral immune response.
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De Paolis, Veronica, Fabio Maiullari, Maila Chirivì, Marika Milan, Chiara Cordiglieri, Francesca Pagano, Alessandra Rita La Manna, et al. "Unusual Association of NF-κB Components in Tumor-Associated Macrophages (TAMs) Promotes HSPG2-Mediated Immune-Escaping Mechanism in Breast Cancer." International Journal of Molecular Sciences 23, no. 14 (July 18, 2022): 7902. http://dx.doi.org/10.3390/ijms23147902.
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The cellular heterogeneity of the tumor environment of breast cancer (BC) is extremely complex and includes different actors such as neoplastic, stromal, and immunosuppressive cells, which contribute to the chemical and mechanical modification of the environment surrounding the tumor-exasperating immune-escaping mechanisms. In addition to molecular signals that make the tumor microenvironment (TME) unacceptable for the penetrance of the immune system, the physical properties of tumoral extracellular matrix (tECM) also have carved out a fundamental role in the processes of the protection of the tumor niche. Tumor-associated macrophages (TAMs), with an M2 immunosuppressive phenotype, are important determinants for the establishment of a tumor phenotype excluded from T cells. NF-κB transcription factors orchestrate innate immunity and represent the common thread between inflammation and cancer. Many studies have focused on canonical activation of NF-κB; however, activation of non-canonical signaling predicts poor survival and resistance to therapy. In this scenario, we demonstrated the existence of an unusual association of NF-κB components in TAMs that determines the deposition of HSPG2 that affects the stiffness of tECM. These results highlight a new mechanism counterbalanced between physical factors and a new perspective of mechano-pathology to be targeted to counteract immune evasion in BC.
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Narasimhan, Harini, Francesca Ferraro, Andreas Bleilevens, Ralf Weiskirchen, Elmar Stickeler, and Jochen Maurer. "Tumor Necrosis Factor-α (TNFα) Stimulate Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model." Biology 11, no. 10 (October 9, 2022): 1481. http://dx.doi.org/10.3390/biology11101481.
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TNBC represents the most aggressive breast cancer subtype. Although cancer stem cells (CSCs) are a minor fraction of all cancer cells, they are highly cancerous when compared to their non-stem counterparts, playing a major role in tumor recurrence and metastasis. Angiogenic stimuli and the tumor environment response are vital factors in cancer metastasis. However, the causes and effects of tumor angiogenesis are still poorly understood. In this study, we demonstrate TNFα effects on primary triple-negative breast cancer stem cells (BCSCs). TNFα stimulation increased the mesenchymality of BCSCs in an intermediate epithelial-to-mesenchymal transition (EMT) state, enhanced proliferation, self-renewal, and invasive capacity. TNFα-treatment elicited BCSC signaling on endothelial networks in vitro and increased the network forming capacity of the endothelial cells. Our findings further demonstrate that TNFα stimulation in BCSCs has the ability to instigate distinct cellular communication within the tumor microenvironment, inducing intra-tumoral stromal invasion. Further, TNFα-treatment in BCSCs induced a pre-metastatic niche through breast-liver organ crosstalk by inducing vascular cell adhesion molecule-1 (VCAM-1) enriched neovasculogenesis in the liver of tumor-bearing mice. Overall, TNFα is an important angiogenic target to be considered in breast cancer progression to attenuate any angiogenic response in the tumor environment that could lead to secondary organ metastasis.
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Solimando, Antonio Giovanni, Matteo Claudio Da Vià, Sebastiano Cicco, Patrizia Leone, Giuseppe Di Lernia, Donato Giannico, Vanessa Desantis, et al. "High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment." Journal of Clinical Medicine 8, no. 7 (July 9, 2019): 997. http://dx.doi.org/10.3390/jcm8070997.
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Multiple myeloma (MM) is a genetically heterogeneous disease that includes a subgroup of 10–15% of patients facing dismal survival despite the most intensive treatment. Despite improvements in biological knowledge, MM is still an incurable neoplasia, and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. The aim of this review is to provide an integrated clinical and biological overview of high-risk MM, discussing novel therapeutic perspectives, targeting the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug-resistance can foster a better tailored clinical management of the high-risk profile and therapy-refractoriness. Among the current clinical difficulties in MM, patients’ management by manipulating the tumor niche represents a major challenge. The angiogenesis and the stromal infiltrate constitute pivotal mechanisms of a mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy, but variable and unpredictable responses in high-risk MM. The comprehensive understanding of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Here, we provide a broad outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better select candidates for dual immune/vasculogenesis targeting.
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Vogel-González, Marina, Dunia Musa-Afaneh, Pilar Rivera Gil, and Rubén Vicente. "Zinc Favors Triple-Negative Breast Cancer’s Microenvironment Modulation and Cell Plasticity." International Journal of Molecular Sciences 22, no. 17 (August 25, 2021): 9188. http://dx.doi.org/10.3390/ijms22179188.
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Triple-negative breast cancer (TNBC) tends to metastasize to the brain, a step that worsens the patient’s prognosis. The specific hallmarks that determine successful metastasis are motility and invasion, microenvironment modulation, plasticity, and colonization. Zinc, an essential trace element, has been shown to be involved in all of these processes. In this work, we focus our attention on the potential role of zinc during TNBC metastasis. We used MDA-MB-BrM2 (BrM2) cells, a brain metastasis model derived from the parental TNBC cell line MDA-MB-231. Our studies show that BrM2 cells had double the zinc content of MDA-MB-231 cells. Moreover, exploring different metastatic hallmarks, we found that the zinc concentration is especially important in the microenvironment modulation of brain metastatic cells, enhancing the expression of SerpinB2. Furthermore, we show that zinc promotes the tumorigenic capacity of breast cancer stem cells. In addition, by causing a disturbance in MDA-MB-231 zinc homeostasis by overexpressing the Zip4 transporter, we were able to increase tumorigenicity. Nevertheless, this strategy did not completely recapitulate the BrM2 metastatic phenotype. Altogether, our work suggests that zinc plays an important role in the transformative steps that tumoral cells take to acquire tumorigenic potential and niche specificity.
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Ortiz, Emiliano, Pablo Sanchis, Juan Bizzotto, Sofia Lage-Vickers, Estefania Labanca, Nora Navone, Javier Cotignola, Elba Vazquez, and Geraldine Gueron. "Myxovirus Resistance Protein 1 (MX1), a Novel HO-1 Interactor, Tilts the Balance of Endoplasmic Reticulum Stress towards Pro-Death Events in Prostate Cancer." Biomolecules 10, no. 7 (July 6, 2020): 1005. http://dx.doi.org/10.3390/biom10071005.
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The inflammatory tumor microenvironment is a fertile niche accelerating prostate cancer (PCa). We have reported that heme-oxygenase (HO-1) had a strong anti-tumoral effect in PCa. We previously undertook an in-depth proteomics study to build the HO-1 interactome in PCa. In this work, we used a bioinformatics approach to address the biological significance of HO-1 interactors. Open-access PCa datasets were mined to address the clinical significance of the HO-1 interactome in human samples. HO-1 interactors were clustered into groups according to their expression profile in PCa patients. We focused on the myxovirus resistance gene (MX1) as: (1) it was significantly upregulated under HO-1 induction; (2) it was the most consistently downregulated gene in PCa vs. normal prostate; (3) its loss was associated with decreased relapse-free survival in PCa; and (4) there was a significant positive correlation between MX1 and HMOX1 in PCa patients. Further, MX1 was upregulated in response to endoplasmic reticulum stress (ERS), and this stress triggered apoptosis and autophagy in PCa cells. Strikingly, MX1 silencing reversed ERS. Altogether, we showcase MX1 as a novel HO-1 interactor and downstream target, associated with ERS in PCa and having a high impact in the clinical setting.
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Kuchar, Martin, Zuzana Strizova, Linda Capkova, Martin Komarc, Jiri Skrivan, Jirina Bartunkova, Daniel Smrz, and Jan Plzak. "The Periphery of Salivary Gland Carcinoma Tumors Reveals a PD-L1/PD-1 Biomarker Niche for the Evaluation of Disease Severity and Tumor—Immune System Interplay." Biomedicines 9, no. 2 (January 20, 2021): 97. http://dx.doi.org/10.3390/biomedicines9020097.
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The treatment options for patients with advanced salivary gland cancers (SGCs) are limited. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, the response to ICI immunotherapy is largely driven by the immune cell signatures within the tumor tissue and the para-tumoral tissue compartments. To date, there are no data on the expression of programed cell death protein-1/programed cell death protein-ligand 1 (PD-1/PD-L1) in SGC, which may enable the implementation of ICI immunotherapy for this disease. Thus, we performed an immunohistochemical analysis of PD-1 and PD-L1 expression in tumor cells and tumor-infiltrating immune cells (TIICs) in the tumor center and periphery of 62 SGC patients. The tumor periphery showed significantly higher expression of PD-L1 in tumor cells than in TIICs. Moreover, peripheral TIICs had significantly higher PD-1 expression than peripheral tumor cells. PD-1-positive tumor cells were detected exclusively in the tumor center of high-grade tumors, and most importantly, the presence of lymph node (LN) metastases and primary tumor stage significantly correlated with the presence of PD-L1-positive tumor cells in the tumor periphery. The PD-1/PD-L1 molecular signatures in SGC are clustered predominantly in the tumor periphery, reflect disease severity, and may predict the response to ICI immunotherapy in SGC patients.
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Woolf, Z., M. Swanson, T. Park, A. Brooks, and M. Dragunow. "P10.02 Differentiating microglia and tumour associated macrophages in high grade glioma." Neuro-Oncology 21, Supplement_3 (August 2019): iii40—iii41. http://dx.doi.org/10.1093/neuonc/noz126.142.
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Abstract BACKGROUND Glioblastoma multiforme (GBM) is the most common primary brain tumour that affects adults. This aggressive tumour is invariably fatal, carrying a rapid progression and a dismal median survival period of only 15 months despite multimodal treatment approaches. Central to GBM pathogenesis is the immunosuppressive profile of these tumours. The two cell types that are highly abundant in these tumours and play critical roles in the immunosuppressive niche are the brain’s resident microglia and their peripheral counterparts - tumour associated macrophages (TAMs). Despite microglia and TAMs being ontogenetically distinct, these cells have largely been grouped together in research owing to the previous lack of cell-specific markers. Recent evidence has suggested that although TAMs may hold a predominantly pro-tumoral role, microglia may adopt a more anti-tumoral phenotype. Therefore, the differentiation of these two cell types is critical in elucidating the potentially characteristic roles of these two cell types in GBM pathogenesis. MATERIAL AND METHODS Tissue sections from resected low- and high-grade glioma tumours, along with epilepsy tissue (control), were used for immunohistochemistry (IHC) staining of macrophage pan-makers (Iba1, CD45, PU.1) and microglial-specific markers (TMEM119, P2RY12). Marker co-localisation was then used to differentiate microglia from TAMs. We further investigated a wider subset of cell-specific markers using multicolour flow cytometry and immunocytochemical staining of isolated cells from patient tissue samples. RESULTS Immunofluorescent staining of glioma and epilepsy tissue revealed two clear populations of cells; one population displayed long processes and co-labelling for both pan- and microglial-specific markers, whilst the other population displayed an amoeboid phenotype with only pan-maker staining. Preliminary analysis comparing microglia/TAM populations in low-grade, high-grade and epilepsy tissue suggests a clear difference in the proportions of these cells. CONCLUSION Our work complements RNA-Seq studies, showing that TMEM119 and P2RY12, alongside other markers, can indeed identify two distinct myeloid cell populations within glioma tissue. This provides a strong basis for further study where we aim to elucidate the respective roles of microglia and TAMs within tumours. Ultimately, this may hold the potential for differential targeting of these cells using immunotherapies.
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Wu, Qiong, Anders E. Berglund, Robert J. MacAulay, and Arnold B. Etame. "A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma." International Journal of Molecular Sciences 23, no. 1 (December 28, 2021): 297. http://dx.doi.org/10.3390/ijms23010297.
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Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM. In this study, we present novel evidence that BIRC3 has an essential noncanonical role in GBM self-renewal and stemness reprogramming. We demonstrate that BIRC3 drives stemness reprogramming of human GBM cell lines, mouse GBM cell lines and patient-derived GBM stem cells (GSCs) through regulation of BMP4 signaling axis. Specifically, BIRC3 induces stemness reprogramming in GBM through downstream inactivation of BMP4 signaling. RNA-Seq interrogation of the stemness reprogramming hypoxic (pseudopalisading necrosis and perinecrosis) niche in GBM patient tissues further validated the high BIRC3/low BMP4 expression correlation. BIRC3 knockout upregulated BMP4 expression and prevented stemness reprogramming of GBM models. Furthermore, siRNA silencing of BMP4 restored stemness reprogramming of BIRC3 knockout in GBM models. In vivo silencing of BIRC3 suppressed tumor initiation and progression in GBM orthotopic intracranial xenografts. The stemness reprograming of both GSCs and non-GSCs populations highlights the impact of BIRC3 on intra-tumoral cellular heterogeneity GBM. Our study has identified a novel function of BIRC3 that can be targeted to reverse stemness programming of GBM.
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Donson, Andrew, Austin Gillen, Riemondy Kent, Ahmed Gilani, Sujatha Venkataraman, Bridget Sanford, Andrea Griesinger, et al. "EPEN-31. SINGLE-CELL RNAseq OF CHILDHOOD EPENDYMOMA REVEALS DISTINCT NEOPLASTIC CELL SUBPOPULATIONS THAT IMPACT ETIOLOGY, MOLECULAR CLASSIFICATION AND OUTCOME." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii314. http://dx.doi.org/10.1093/neuonc/noaa222.167.
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Abstract Ependymoma (EPN) is a brain tumor commonly presenting in childhood that remains fatal in the majority of children. Intra-tumoral cellular heterogeneity in bulk-tumor samples significantly confounds our understanding of EPN biology, impeding development of effective therapy. We therefore used single-cell RNA sequencing to catalog cellular heterogeneity of 26 childhood EPN, predominantly from ST-RELA, PFA1 and PFA2 subgroups. ST-RELA and PFA subgroups clustered separately, with ST-RELA clustering largely according to individual sample-of-origin. PFA1 and PFA2 subgroup EPNs cells were intermixed and revealed 4 major subpopulations – 2 with characteristics of ependymal differentiation (transporter and ciliated phenotype subpopulations), an undifferentiated subpopulation and a mesenchymal phenotype. Pseudotime analysis showed the undifferentiated progenitor subpopulation either differentiating into ependymal differentiation subpopulations or transitioning into the mesenchymal subpopulation. Histological analysis revealed that undifferentiated and mesenchymal subpopulations cells colocalized to perinecrotic/perivascular zones, the putative ependymoma stem cell niche. Deconvolution of PFA bulk transcriptome data showed that undifferentiated and mesenchymal subpopulations were associated with a poor prognosis; whereas the ciliated ependymal cell-differentiated subpopulation was associated with a good prognosis. In conflict with current distinct classification paradigms, the ratio of mesenchymal and ciliated subpopulations determined bulk-tumor subgroups assignment to PFA1 and PFA2 respectively. This atlas of EPN cellular heterogeneity provides an important advance in our understanding of EPN biology, identifying high-risk associated subpopulations for therapeutic targeting.
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Mansouri, Sheila, Shreya Gandhi, Mark Zaidi, Olivia Singh, Shirin Karimi, Phoebe Lombard, Anna Dvorkin-gheva, et al. "TMIC-82. SPATIAL AND SINGLE-CELL PROTEOMIC LANDSCAPING OF THE HYPOXIC MICROENVIRONMENT IN GLIOBLASTOMA." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v296—v297. http://dx.doi.org/10.1093/neuonc/noad179.1147.
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Abstract Glioblastoma (GBM) is a fatal adult solid tumour with median overall survival of 18-20 months post-diagnosis; contributing factors to therapeutic inefficacy include acquisition of genomic alterations post-therapy, immune evasion, deregulated hypervascularization, and tumor microenvironmental factors such as hypoxia. Combined with extensive inter- and intra-tumoral heterogeneity at bulk and single-cell level, hypoxia contributes to a gradient of molecular alterations that are specific to different cell populations that make up tumour bulk and reside in specific niches. Hitherto, high-dimensional histopathologic analyses of hypoxic regions within GBM tissue have not been performed. We took a combined spatial and single-cell proteomic profiling approach to investigate the histopathologic features of hypoxia by leveraging a unique clinical study wherein the exogenous hypoxia marker, pimonidazole (PIMO), was administered to GBM-patients preoperatively. Tissue specimens were subjected to imaging mass cytometry, high-resolution imaging, and serial immunohistochemistry using a panel of markers associated with cellular hallmarks of hypoxia, metabolism, proliferation, stemness, angiogenesis, and immune cell types. Our findings showed that PIMO staining is associated with histopathologic features of hypoxia and correlates with specific metabolic, immune, and stemness markers in GBM; specific lymphocyte populations were depleted from hypoxic regions alongside alterations in macrophagic and microglial landscape in a niche-specific manner; hypoxia reduced the proportion of proliferating glioma initiating cells and altered the proliferative, transcriptional, and translational capacity of different cell populations; microvessel density was reduced in hypoxic microenvironment. Cytometry by time-of-flight further validated the altered proportions of specific immune cell types enriched in hypoxic populations of GBM microenvironment. Our study is the first to report use of PIMO to interrogate spatial, single-cell, and phenotypic architecture associated with tissue hypoxia and altered expression of biomarkers associated with hypoxia/glycolysis, immune infiltration, proliferation, and stemness. Identification of targetable biomarkers and mediators of hypoxia-driven habitats in GBM may provide direction for future immunotherapeutic research.
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Kim, Ji-Yeon, Sabin Park, Sepil Ahn, Eun Seop Seo, Soyeon Kim, Mark Gregory, Emily Killingbeck, et al. "Abstract 7644: Prognostication of genomic characteristics of residual breast cancer after neoadjuvant chemotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7644. http://dx.doi.org/10.1158/1538-7445.am2024-7644.
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Abstract Residual cancer burden (RCB) based on pathologic characteristics is the most powerful prognostic factor in breast cancer (BC) which received neoadjuvant chemotherapy (NAC) followed by surgery. According to RCB classification, class III predicted short survival duration regardless of BC subtypes according to hormone receptor (HR) and human epidermal growth factor receptor-2 (HER-2) state. However, up to 20-40% of BCs with RCB class III did not experience BC recurrence and had long term survival without disease recurrence. In our study, we evaluated genomic characteristics of BC which had high RCB class. We collected 96 fresh frozen BC specimens which had undergone surgery after NAC between 2010 and 2018 from Samsung Medical Center Biobank. We performed whole genome or exome sequencing, RNA sequencing and high-plex single-cell spatial transcriptomics. Of 96 BCs, 65 BCs had experienced BC recurrence and 31 BCs have not been BC recurrence. Of 65 BCs with dismal prognosis, 12 were HR+HER2-, four in HR+HER2+, 39 in triple negative breast cancer (TNBC) and 10 in HR-HER2+ BC. Of 31 BCs without recurrence, 11 were HR+HER2-, two in HR+HER2+, 14 in TNBC and four in HR-HER2+ BC. In HR+HER2- BC, ten of 12 BCs with dismal prognosis were categorized into basal like intrinsic subtype and two were into luminal B subtype compared that six of luminal A and five of luminal B subtype categorization in good prognosis BC group. Age associated mutation signature were enriched in HR+HER2- BC with good prognosis (p=0.027). Tumor microenvironment (TME) analysis using Kassandra suggested that high monocytes were associated with BC with dismal prognosis (p=0.00031). In single-cell spatial transcriptome analysis, T-cell abundance in the tumoral niche is associated with dismal prognosis in HR+HER2- BC (p=0.039). In TNBC, almost BCs (88.7%) were categorized into basal-like intrinsic subtype regardless of their prognosis. TME analysis presented that immune cells including macrophages and lymphocytes with CD4 and CD8 T cells were significantly enriched in TNBC with good prognosis (ps <0.05, respectively). In HER2+ BC, intrinsic subtypes were heterogeneous in both groups. Focal amplification in HER2+BC patient harbored DNA segments from different chromosomes more frequently than in those with good prognosis (p=0.00091), which was prominent in oncogenic extrachromosomal DNA amplifications compared to other oncogenic amplifications. In TME analysis, there were no specific cell enrichments according to BC prognosis but sing-cell spatial transcriptome analysis revealed that higher T-cell abundance in the tumoral niche was associated with HR+HER2+ BC with good prognosis (p=0.047). In conclusion, each BC subtype had their own genomic characteristics to determine their prognosis. Our study also suggested that TME characteristics was common prognostic factor for survival outcome of BC with residual tumor after NAC. Citation Format: Ji-Yeon Kim, Sabin Park, Sepil Ahn, Eun Seop Seo, Soyeon Kim, Mark Gregory, Emily Killingbeck, Eun Yoon Cho, Jeong Eon Lee, Jin Seok Ahn, Yeon Hee Park, Woong-Yang Park, Hoon Kim, Semin Lee, Young-Hyuck Im. Prognostication of genomic characteristics of residual breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7644.
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Onuchic, Ana Cláudia, and Roger Chammas. "Câncer e o microambiente tumoral." Revista de Medicina 89, no. 1 (March 19, 2010): 21–31. http://dx.doi.org/10.11606/issn.1679-9836.v89i1p21-31.
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Antes tido como um conjunto de células alteradas em proliferação, hoje o câncer é mais bem entendido como um microambiente, em que as interações entre os elementos celulares e moleculares que o compõem são determinantes na progressão tumoral. Como resultado, a compreensão do evento neoplásico ganha complexidade crescente. A dinâmica das células tumorais passa a ser avaliada como parte de um verdadeiro tecido tumoral, sujeita a condições de vascularização, de oxigenação, de pressão intersticial e de necrose tecidual, que influenciam na cinética tumoral. Estão sendo identificados novos componentes deste nicho tumoral e as suas respectivas atuações. Entre esses integrantes, encontram-se os elementos da imunidade, cuja modulação tem sido demonstrada por uma série de pesquisas aqui revisadas, tanto no sentido da vigilância imunológica, como pressão seletiva negativa, quanto no favorecimento da progressão tumoral. Esta revisão analisará a neoplasia do ponto de vista de um microambiente tumoral, focando na participação imunológica e na cinética tumoral, expondo as principais idéias e descobertas que criaram e estão aperfeiçoando o conceito de câncer
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Vicenzi, Silvia, Trung Tran, Lara Avsharian, Joshua Hartman, Anna Rapp, and Leslie Crews. "Tuning the Innate Immune Multiple Myeloma Microenvironment By Modulating IRF4." Blood 142, Supplement 1 (November 28, 2023): 6604. http://dx.doi.org/10.1182/blood-2023-187814.
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The tumor microenvironment (TME) has emerged as a key contributor to cancer progression in numerous solid tumors as well as blood cancers that evolve in the bone marrow (BM). In the context of multiple myeloma (MM), survival of malignant plasma cells is supported by interactions with the BM microenvironment, which is comprised of various components including cells, extracellular matrix, and soluble factors. Therefore, the development of strategies that specifically target the MM BM microenvironment is crucial for improving current disease prognosis. Within the BM niche, M2-like myeloma-associated macrophages (MAMs) play a significant role in cancer cell survival and progression and have been implicated in producing an immune-suppressive TME by generating inflammatory mediators, growth factors, cytokines, chemokines, etc. Macrophages exhibit plasticity with regard to their polarization state, which enable them to dynamically respond and adapt to different environmental stimuli in order to fulfill important immune functions. Thus, the reprogramming of M2-like, pro-tumoral MAMs toward a M1-like, anti-tumoral phenotype represents a promising therapeutic strategy. In MM, inflammatory and anti-viral pathways promote disease progression. Interferon regulatory factor 4 (IRF4) is a transcription factor that has previously been shown to promote MM progression through enhanced survival of malignant plasma cells. Under physiological conditions, IRF4 also regulates macrophage polarization, where its expression drives alternative activation of macrophages primarily to M2-like (anti-inflammatory) phenotypes. However, the extent to which IRF4 activation or direct inhibition governs the polarization status and pro-tumoral activity of macrophages in the MM microenvironment has not been fully elucidated. In this study, we sought to further explore the role of IRF4 in macrophage polarization and investigated the potential of modulating IRF4 expression to reprogram myeloma-associated macrophages (MAMs) as a novel therapeutic strategy. First, we developed myeloma-tailored macrophage polarization models using primary human peripheral blood-derived monocytes and the THP1 monocyte cell line. Our M1 and M2 polarization models utilize a customized cocktail of myeloid growth factors and cytokines, supplemented with interleukin (IL)-6 to mimic the IL-6-enriched MM microenvironment. Characterization of M1 (CD80, TNFα, and CXCL10) and M2 (MRC1, FN1, and CCL22) markers confirmed the presence of distinct macrophage subpopulations, as well as upregulated expression of IRF4 in M2-like progeny and IRF5 in M1-like macrophages. To investigate the extent to which IRF4 activation or direct inhibition governs macrophage polarization and function, overexpression and knockdown experiments on macrophages were performed in vitro, along with whole transcriptome sequencing of IRF4-overexpressing THP1 monocytes compared to vector-transduced controls. Gene expression analyses revealed that genetic down-modulation of IRF4 in M2-like macrophages shifts the polarization status toward a hybrid phenotype that displays enhanced M1-like properties, while still retaining M2-like characteristics. This shift in polarization state was further amplified when monocytes were transduced to overexpress IRF4 prior to differentiation into M2-like macrophages and subsequent IRF4 knockdown, suggesting that IRF4 plays a key regulatory role in tuning macrophage polarization. Taken together, our preclinical findings provide groundwork for future studies on MAMs and suggest that an IRF4-mediated macrophage reprogramming strategy is a promising therapeutic approach for patients with MM and a variety of other malignancies typified by an anti-inflammatory TME.
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Jibril, Aisha, Jayna J. Mistry, Jamie A. Moore, Charlotte Hellmich, Victoria Willimott, Kristian M. Bowles, and Stuart A. Rushworth. "Myeloma Derived Mitochondrial Damage Associated Molecular Patterns Promote Pro-Tumoral Expansion By Inducing a Pro-Inflammatory Signature in the Bone Marrow Microenvironment." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-139811.
Full textAbstract:
Multiple Myeloma (MM) is a malignancy of antibody producing B cells (plasma cells), leading to the accumulation of tumour cells within the bone marrow (BM) microenvironment. Mitochondrial DNA (mtDNA) is a damage associated molecular pattern (DAMP), the mitochondrial genome contains islands of unmethylated CpG nucleotide motifs that have been shown to activate and promote memory B cell proliferation and antibody secretion. Recent studies have indicated that mtDNA is elevated in the circulation of trauma and cancer patients and have highlighted the need to determine the functional purpose of elevated mtDNA within the BM microenvironment. Here we investigate the hypothesis that multiple myeloma cells secrete mtDNA and other mtDAMPs to induce a pro-inflammatory bone marrow microenvironment, supportive of the progression and survival of MM. As well as investigating how MM affects the haematopoietic stem cell niche through establishing a syngeneic myeloma mouse model. We show that immunocompromised NSG mice transplanted with human MM cell lines released higher levels of MM derived mtDNA detected in the plasma by real-time PCR. Furthermore, in vitro experiments showed that pro-inflammatory cytokines IL-1B, IL-6, and IL-8 were elevated in both primary and cell line myeloma samples upon treatment with CpG oligonucleotides. Murine bone marrow derived macrophages (BMDMs) treated with mtDNA or mtDAMPs showed increased expression of pro-inflammatory cytokines. To understand the significance of the mtDAMP proinflammatory induction, C57BL/6 mice were successfully engrafted with murine 5TGM1 myeloma cell line to establish a syngeneic mouse model. Analysis of the haematopoietic stem and progenitor cell populations showed that 5TGM1 induced the expansion of these cell populations when compared to control WT animals. To understand the significance of mtDAMPs in regulating this HSPC expansion we used blocking antibodies to TLR9 (receptor for mtDNA) and FPR1 (receptor for formylated mitochondrial proteins) in 5TGM1 engrafted animals. Results show that myeloma tumour burden was reduced when FPR1 and TLR9 are blocked compared to control animals. Here we highlight the involvement of mtDAMPs in MM to create a favourable proinflammatory microenvironment which provides the conditions for MM survival and proliferation. This data highlights the importance of mtDAMPs in MM disease progression and suggests targeting these activating receptor pathways may provide a novel therapeutic intervention. Disclosures Bowles: Janssen: Research Funding; AbbVie: Research Funding. Rushworth:Janssen: Research Funding; AbbVie: Research Funding.