Letteratura scientifica selezionata sul tema "Neuroendocrine transdifferentiation"
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Articoli di riviste sul tema "Neuroendocrine transdifferentiation"
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Sergeant, Camille, Christel Jublanc, Delphine Leclercq, et al. "Transdifferentiation of Neuroendocrine Cells." American Journal of Surgical Pathology 41, no. 6 (2017): 849–53. http://dx.doi.org/10.1097/pas.0000000000000803.
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Stone, Louise. "A novel mechanism of neuroendocrine transdifferentiation." Nature Reviews Urology 15, no. 5 (2018): 263. http://dx.doi.org/10.1038/nrurol.2018.40.
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Cordeiro-Rudnisky, Fernanda, Yue Sun, and Rayan Saade. "Prostate Carcinoma With Overlapping Features of Small Cell and Acinar Adenocarcinoma: A Case Report." American Journal of Clinical Pathology 152, Supplement_1 (2019): S66—S67. http://dx.doi.org/10.1093/ajcp/aqz113.072.
Testo completoAbstract (sommario):
Abstract Introduction Prostate neuroendocrine (NE) cells can stimulate prostate adenocarcinoma (PA) cell growth, but occasionally adenocarcinoma cells themselves acquire NE characteristics, a phenomenon known as NE transdifferentiation of prostate adenocarcinoma. During this process, tumor cells acquire small cell-like morphology and become positive for neuroendocrine markers. NE transdifferentiation is associated with decreased androgen receptor (AR) signaling, a mechanism of resistance to AR-targeted treatments. Case A 74-year-old male with a history of cirrhosis, splenomegaly, and thrombocytopenia presented with hematuria and urinary obstruction. PSA was 0.31 ng/mL. CT scan demonstrated bladder wall thickening. Surgery showed a bladder tumor, clinically diagnosed as urothelial tumor. Pathology revealed a poorly differentiated carcinoma, with small cell-like morphology. The tumor cells had high nuclear to cytoplasmic ratio, focal nuclear molding, and high mitotic rate, like small cell carcinoma. But the nucleoli were intermediate between small cell carcinoma and usual adenocarcinoma of the prostate. Immunostains showed that the tumor cells were positive for NKX3.1 and focally positive for NE markers, including chromogranin, synaptophysin, INSM1, and FOXA2. The tumor cells were negative for PSA and GATA3. The morphology and immunoprofile are consistent with Gleason pattern 5 PA in transdifferentiation to small cell carcinoma. Discussion The incidence of neuroendocrine phenotype is 1% in primary PA and 25% in metastatic castrate-resistant PA. Typically, NE transdifferentiation occurs in response to androgen deprivation therapy/AR inhibitors. Pretreatment NE transdifferentiation is relatively uncommon. PA depends on androgens for its progression, which is the basis for antiandrogen therapy. Decreased AR expression associated with NE transdifferentiation is a mechanism of resistance to AR-targeted therapy. These tumors are often more aggressive with worse prognosis. Conclusion Our patient has Gleason pattern 5 PA with NE transdifferentiation invading the bladder, which is a high-grade, aggressive tumor.
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Quintanal-Villalonga, Alvaro, Hirokazu Taniguchi, Yingqian A. Zhan, et al. "AKT inhibition as a therapeutic strategy to constrain histological transdifferentiation in EGFR-mutant lung adenocarcinoma." Journal of Clinical Oncology 40, no. 16_suppl (2022): e21166-e21166. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21166.
Testo completoAbstract (sommario):
e21166 Background: In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation. Methods: We performed multi-omic profiling of LUAD-to-LUSC and LUAD-to-NE transdifferentiating clinical samples, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Clinical findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Results: Our data supports that histological transdifferentiation from LUAD to LUSC or NE tumors is driven by epigenetic remodeling rather than by mutational events, and indicate that transdifferentiated tumors retain epigenomic features of their previous LUAD state. Integrative epigenomic, transcriptomic and protein analysis revealed divergent biological pathways dysregulated for each histological outcome, such as downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses identified commonly dysregulated pathways in both NE- and LUSC-transdifferentiating tumors, including remarkable downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in different EGFR-mutant patient-derived xenograft transdifferentiation models. Conclusions: These results identify common and divergent dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation.
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Yuan, Ta-Chun, Suresh Veeramani, and Ming-Fong Lin. "Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells." Endocrine-Related Cancer 14, no. 3 (2007): 531–47. http://dx.doi.org/10.1677/erc-07-0061.
Testo completoAbstract (sommario):
Neuroendocrine (NE) cells represent a minor cell population in the epithelial compartment of normal prostate glands and may play a role in regulating the growth and differentiation of normal prostate epithelia. In prostate tumor lesions, the population of NE-like cells, i.e., cells exhibiting NE phenotypes and expressing NE markers, is increased that correlates with tumor progression, poor prognosis, and the androgen-independent state. However, the origin of those NE-like cells in prostate cancer (PCa) lesions and the underlying molecular mechanism of enrichment remain an enigma. In this review, we focus on discussing the distinction between NE-like PCa and normal NE cells, the potential origin of NE-like PCa cells, and in vitro and in vivo studies related to the molecular mechanism of NE transdifferentiation of PCa cells. The data together suggest that PCa cells undergo a transdifferentiation process to become NE-like cells, which acquire the NE phenotype and express NE markers. Thus, we propose that those NE-like cells in PCa lesions were originated from cancerous epithelial cells, but not from normal NE cells, and should be defined as ‘NE-like PCa cells’. We further describe the biochemical properties of newly established, stable NE-like lymph node carcinoma of the prostate (LNCaP) cell lines, transdifferentiated from androgen-sensitive LNCaP cells under androgen-deprived conditions. Knowledge of understanding NE-like PCa cells will help us to explore new therapeutic strategies for treating PCa.
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Von Amsberg, Gunhild, Sergey Dyshlovoy, Jessica Hauschild, et al. "Long-term taxane exposure and transdifferentiation of prostate cancer in vitro." Journal of Clinical Oncology 41, no. 6_suppl (2023): 254. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.254.
Testo completoAbstract (sommario):
254 Background: Development of aggressive variants of metastatic castration-resistant prostate cancer (AVPC) is a major challenge in the course of therapy but the underlying mechanisms of aggressive transdifferentiation are not completely understood and appropriate tumor models are missing. Here, we investigated the consequences of long-term taxane exposure on hormone-independent, BRCA2-mutated, AR-V7-positive 22Rv1 cells. Methods: 22Rv1 cells were treated with stepwise increased taxane concentrations for 10 months. Individual clones were picked and further cultured in media containing either docetaxel (Doce) or cabazitaxel (Caba). Passage-matched cells were maintained in culture without treatment. Further characterization was carried out using proliferation, migration, metabolic, and colony formation assays as well as proteomics, RNAseq analyses and xenotransplantation in immunodeficient mice. Results: In total, three single cell 22Rv1-DR clones (50-100-fold resistance to Doce) and three 22Rv1-CR clones (80-150-fold resistance to Caba) were successfully established. All clones showed cross-resistance to either drug. Expectedly, treatment-induced overexpression of ABCB1 was detected and validated. Moreover, alteration of drug resistance related SLC7A5, SLC3A2, and SLC25A24 genes was observed. Additionally, an enrichment analyses identified, among others, neuroendocrine transdifferentiation (GO-term “Neuroendocrine tumors”, p=4.46e-5) to be stimulated in prostate 22Rv1 cells under long-term treatment with Doce or Caba. In line with this, the neuroendocrine features were validated in vitro as well as in xenotransplanted tumors in vivo with upregulation of synaptophysin, chromogranin and neuron specific enolase accompanied by downregulation of the androgen receptor (AR) and upregulation of AR spice variants. Additionally, neuritic morphology, shift to higher nuclear-plasma ratio, partial loss of adherent properties and growth slowdown, along with higher migratory activity were detected. Conclusions: Long-term taxane exposure of 22Rv1 cells resulted in the development of neuroendocrine traits in individual cell clones that have successfully been translated into stable cell lines. Thus, we provide a new cell line model for secondary therapy-induced neuroendocrine transdifferentiation. Further in-depth analysis to identify individual alterations in the course of therapy is currently ongoing.
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Quintanal-Villalonga, Alvaro, Hirokazu Taniguchi, Yingqian A. Zhan, et al. "Abstract 658: AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation." Cancer Research 82, no. 12_Supplement (2022): 658. http://dx.doi.org/10.1158/1538-7445.am2022-658.
Testo completoAbstract (sommario):
Abstract Lineage plasticity contributes to therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon drives neuroendocrine (NE) and squamous cell (LUSC) histologic transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is lower than that of either LUAD or de novo LUSC patients. To date, little is known about the molecular effectors enhancing lineage plasticity and driving histological transdifferentiation due to the paucity of well annotated pre- and post-transdifferentiation clinical samples amenable for molecular analyses. Currently no specific therapies for LUSC or NE transdifferentiation prevention are available for patients at high risk of transformation. We performed multi-omic profiling of transdifferentiating clinical samples, as well as control never-transformed LUAD and de novo LUSC and small cell carcinomas, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Our data suggest that histological transdifferentiation is driven by epigenetic -rather than mutational- events, and indicate that transdifferentiated tumors retain molecular features of their previous LUAD state. Integrative analysis revealed biological pathways dysregulated specifically for distinct histological outcomes, including downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses revealed commonly dysregulated pathways for transdifferentiated tumors, including marked downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in EGFR-mutant patient-derived xenograft transdifferentiation models. These results identify common and histology-specific drivers and dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to constrain lineage plasticity and prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation. Citation Format: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yingqian A. Zhan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Umesh K. Bhanot, Jacklynn Egger, Juan Qiu, Elisa de Stanchina, Natasha Rekhtman, Brian Houck-Loomis, Richard P. Koche, Helena A. Yu, Triparna Sen, Charles M. Rudin. AKT pathway as a therapeutic target to constrain lineage plasticity leading to histological transdifferentiation [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 658.
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Frigo, Daniel E., and Donald P. McDonnell. "Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation." Molecular Cancer Therapeutics 7, no. 3 (2008): 659–69. http://dx.doi.org/10.1158/1535-7163.mct-07-0480.
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Patel, Girijesh, Sayanika Dutta, Mosharaf Mahmud Syed, et al. "TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p." Cancers 13, no. 19 (2021): 5020. http://dx.doi.org/10.3390/cancers13195020.
Testo completoAbstract (sommario):
Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.
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Turner, Leo, Andrew Burbanks, and Marianna Cerasuolo. "Mathematical insights into neuroendocrine transdifferentiation of human prostate cancer cells." Nonlinear Analysis: Modelling and Control 26, no. 5 (2021): 884–913. http://dx.doi.org/10.15388/namc.2021.26.24441.
Testo completoAbstract (sommario):
Prostate cancer represents the second most common cancer diagnosed in men and the fifth most common cause of death from cancer worldwide. In this paper, we consider a nonlinear mathematical model exploring the role of neuroendocrine transdifferentiation in human prostate cancer cell dynamics. Sufficient conditions are given for both the biological relevance of the model’s solutions and for the existence of its equilibria. By means of a suitable Liapunov functional the global asymptotic stability of the tumour-free equilibrium is proven, and through the use of sensitivity and bifurcation analyses we identify the parameters responsible for the occurrence of Hopf and saddle-node bifurcations. Numerical simulations are provided highlighting the behaviour discovered, and the results are discussed together with possible improvements to the model.
Tesi sul tema "Neuroendocrine transdifferentiation"
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Guo, Yingbo. "Rôle du cil primaire au cours de la transdifferentiation neuroendocrine du cancer de la prostate." Electronic Thesis or Diss., Université Côte d'Azur, 2024. http://www.theses.fr/2024COAZ6005.
Testo completoAbstract (sommario):
Le cancer de la prostate est l’un des cancers malins les plus répandus dans le monde, avec 95 % des patients diagnostiqués présentant un adénocarcinome de la prostate sans marqueurs neuroendocriniens. Le cancer neuroendocrinien de la prostate de novo représente un sous-type rare et agressif. Environ 20 % des cas d’adénocarcinome de la prostate évoluent vers le cancer neuroendocrinien de la prostate après un traitement de privation androgénique. Le traitement de privation androgénique bien qu’efficace, peut également induire une différenciation neuroendocrinienne de l'adénocarcinome de la prostate, présentant ainsi un nouveau défi pour le traitement du cancer de la prostate. Bien que de nombreux mécanismes moléculaires de la différenciation neuroendocrinienne aient été décrits, le moment précis de l’occurrence de la différenciation neuroendocrinienne et les facteurs qui la déterminent restent encore largement inconnus.Le cil primaire est un organite non mobile présent dans presque toutes les cellules humaines. Sa perte est observée dans différents cancers, notamment le carcinome rénal à cellules claires (ccRCC) et le cancer de la prostate. Les recherches antérieures de notre équipe ont identifié un sous-groupe particulier de patients développant un ccRCC qui exprimait le cil primaire et présentait une résistance aux traitements. La présence du cil primaire était caractérisée par la signature GLI1+/IFT20+. Une corrélation a été observée entre la présence du cil primaire et l’agressivité du ccRCC. Étant donné que le ccRCC et le cancer de la prostate sont généralement considérés comme des cancers dépourvus du cil primaire, nous avons émis l'hypothèse de l’existence d’un sous-groupe spécifique de patients développant un cancer de la prostate pourrait présenter du cil primaire, associée à une agressivité accrue.Nous avons établi plusieurs approches afin d’augmenter le pourcentage de cellules ciliées à la fois dans les cellules prostatiques normales et les cellules semblables au cancer de la prostate dans des cultures cellulaires en 2D ou 3D. Cette augmentation était associée à l'inhibition de la prolifération et de la croissance de la structure en 3D. Notamment, ces approches ont conservé leur capacité à induire la formation de cils primaires, même dans des conditions hypoxiques. Nos résultats ont confirmé la robustesse de la signature GLI1+/IFT20+ pour augmenter la formation de cils primaires dans les cellules normales, tandis que cette signature était moins prononcée dans les cellules semblables au cancer de la prostate. Dans un modèle de cellules cancéreuses de la prostate, nous avons découvert que la restauration du cil primaire est associée à la transdifférenciation neuroendocrine du cancer de la prostate. De plus, la régulation du cil primaire est corrélée à l'agressivité du cancer.Nos recherches démontrent que le cil primaire est présent dans un sous-groupe de patients exprimant un cancer de la prostate plus agressif, tout comme dans le ccRCC. La caractérisation du cil primaire dans la transdifférenciation du cancer de la prostate offre de nouvelles perspectives sur le traitement du cancer de la prostate<br>Prostate cancer is one of the most common malignancy cancers worldwide. 95% of PCa patients are diagnosed with adenocarcinoma of the prostate showing no expression of neuroendocrine markers. De novo neuroendocrine prostate cancer is a rare and aggressive subtype of prostate cancer, characterized by neuroendocrine markers expression. Approximatively 20% of adenocarcinoma cases progress to neuroendocrine prostate cancer following androgen deprivation therapy. The potential side effect of androgen deprivation therapy, resulting in neuroendocrine differentiation of adenocarcinoma of the prostate, brings a novel challenge for prostate cancer treatment. While many molecular mechanisms of neuroendocrine differentiation have been described, the timing of the neuroendocrine differentiation occurrence and how these driving factors result in neuroendocrine differentiation remain unclear.The primary cilium is a non-motile organelle present in nearly all human cells. Loss of primary cilium has been observed in various cancers, including clear cell Renal Cell Carcinoma (ccRCC) and PCa. Previous findings from our research team identified a distinct subgroup of pataients within ccRCC, which retained primary cilium and exhibited resistance to therapy. The presence of primary cilium was characterized by the GLI1+/IFT20+ signature. Under hypoxic conditions, primary cilium was inhibited due to stabilization of HIF-1α, correlating with increased aggressiveness of ccRCC. Considering that both ccRCC and prostate cancer are typically described as cancer lacking PC, we postulated the existence of a unique subgroup in prostate cancer exhibiting primary cilium presence associated with higher aggressiveness.We developed multiple approaches to enhance in the number of primary cilium numbers in both normal prostate cells and prostate cancer-like cells in 2D or 3D cell culture settings. This increase was correlated with a reduction in proliferation and growth of 3D structures. Notably, these methods maintained their effectiveness in inducing primary cilium numbers even under hypoxic conditions. Our findings confirmed the robustness of the GLI1+/IFT20+ signature in increasing primary cilium numbers in normal cells, while this signature was less pronounced in prostate cancer-like cells. In parallel, we discovered that the restoration of primary cilium in prostate cancer cells is associated to the neuroendocrine transdifferentiation of prostate cancer. Furthermore, the regulation of primary cilium is linked to the cancer aggressiveness.Our research provides evidence that primary cilium is present in a more aggressive subgroup of prostate cancer patients, similar to what is observed in ccRCC. Analyzing the role of primary cilium in the transdifferentiation of prostate cancer provides new insights into potential treatment strategies
Atti di convegni sul tema "Neuroendocrine transdifferentiation"
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Li, Yinan. "Abstract 4473: SRRM4 drives treatment-induced neuroendocrine transdifferentiation of prostate adenocarcinoma under androgen receptor pathway inhibition." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4473.
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Beshiri, Mike L., Caitlin M. Tice, Adam G. Sowalsky, et al. "Abstract 5020: A patient-derived organoid model of neuroendocrine prostate cancer transdifferentiation informing the role of the BAF complex component ARID1A." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5020.
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