Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46

AbstractNeuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.

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MicroRNA-1205 Regulation of FRYL in Prostate Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.647485 ◽

2021 ◽

Vol 9 ◽

Author(s):

Michelle Naidoo ◽

Fayola Levine ◽

Tamara Gillot ◽

Akintunde T. Orunmuyi ◽

E. Oluwabunmi Olapade-Olaopa ◽

...

Keyword(s):

Prostate Cancer ◽

Neuroendocrine Differentiation ◽

Castration Resistant Prostate Cancer ◽

Chromosomal Locus ◽

Protein Coding ◽

Castration Resistant ◽

Dendritic Branching ◽

Very High

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (CRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). The 8q24 chromosomal locus is a region of very high PCa susceptibility that carries genetic variants associated with high risk of PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes a cluster of microRNAs including, microRNA-1205 (miR-1205), which are largely understudied. Herein, we demonstrate that miR-1205 is underexpressed in PCa cells and tissues and suppresses CRPC tumors in vivo. To characterize the molecular pathway, we identified and validated fry-like (FRYL) as a direct molecular target of miR-1205 and observed its overexpression in PCa cells and tissues. FRYL is predicted to regulate dendritic branching, which led to the investigation of FRYL in neuroendocrine PCa (NEPC). Resistance toward ADT leads to the progression of treatment related NEPC often characterized by PCa neuroendocrine differentiation (NED), however, this mechanism is poorly understood. Underexpression of miR-1205 is observed when NED is induced in vitro and inhibition of miR-1205 leads to increased expression of NED markers. However, while FRYL is overexpressed during NED, FRYL knockdown did not reduce NED, therefore revealing that miR-1205 induces NED independently of FRYL.

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Neuroendocrine differentiation markers guide treatment sequence selection in metastatic castration‐resistant prostate cancer

The Prostate ◽

10.1002/pros.23762 ◽

2019 ◽

Vol 79 (6) ◽

pp. 567-573 ◽

Cited By ~ 3

Author(s):

Liancheng Fan ◽

Yan Yang ◽

Chenfei Chi ◽

Xiaowei Ma ◽

Rui Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Neuroendocrine Differentiation ◽

Treatment Sequence ◽

Castration Resistant Prostate Cancer ◽

Differentiation Markers ◽

Castration Resistant ◽

Sequence Selection

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Neuroendocrine differentiation in castration resistant prostate cancer. Nuclear medicine radiopharmaceuticals and imaging techniques: A narrative review

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2019.03.005 ◽

2019 ◽

Vol 138 ◽

pp. 29-37 ◽

Cited By ~ 2

Author(s):

Sharjeel Usmani ◽

Marina Orevi ◽

Antonella Stefanelli ◽

Alberto Zaniboni ◽

Ofer Nathan Gofrit ◽

...

Keyword(s):

Prostate Cancer ◽

Nuclear Medicine ◽

Imaging Techniques ◽

Neuroendocrine Differentiation ◽

Narrative Review ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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MicroRNA determinants of neuroendocrine differentiation in metastatic castration-resistant prostate cancer

Oncogene ◽

10.1038/s41388-020-01493-8 ◽

2020 ◽

Vol 39 (49) ◽

pp. 7209-7223

Author(s):

Divya Bhagirath ◽

Michael Liston ◽

Nikhil Patel ◽

Theresa Akoto ◽

Byron Lui ◽

...

Keyword(s):

Prostate Cancer ◽

Neuroendocrine Differentiation ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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IL1B loss is associated with increased AR activity in castration-resistant prostate cancer

10.1101/2021.08.31.458406 ◽

2021 ◽

Author(s):

Wisam N. Awadallah ◽

Jagpreet S. Nanda ◽

Sarah E. Kohrt ◽

Magdalena M Grabowska

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cancer Cells ◽

Marker Gene ◽

Neuroendocrine Differentiation ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Expression And Activity

Castration-resistant prostate cancer represents a continuum of phenotypes, including tumors with high levels of androgen receptor (AR) expression and activity and those which do not express AR and rely on alternative pathways for survival. The process by which AR-positive prostate cancer cells and tumors lose AR expression and acquire neuroendocrine features is referred to as neuroendocrine differentiation. Numerous therapies and exposures have been demonstrated to induce neuroendocrine differentiation in vitro, including the pro-inflammatory cytokine, interleukin 1 beta (IL-1β), encoded by the gene IL1B. The purpose of our studies was to determine the relationship between the expression and activity of AR in relationship to IL-1β and IL1B in prostate cancer. We performed analysis of de-identified human clinical data and generated prostate cancer cell lines with overexpression or knockout of IL1B. In primary prostate cancer, higher expression of IL1B predicts longer time to biochemical recurrence. In metastatic castration-resistant prostate cancer, IL1B expression is decreased and inversely correlates with AR and AR-target gene expression and AR activity, while positively correlating with the neuroendocrine prostate cancer (NEPC) score and neuroendocrine marker gene expression. In vitro, we report that AR-positive castration-resistant prostate cancer cells (C4-2B, 22Rv1) secrete IL-1β, and knockout of IL1B in these cells results in increased AR activity, in the presence and absence of dihydrotestosterone (DHT). Importantly, knockout of IL1B prevented AR attrition during androgen-deprivation. Taken together, our studies demonstrate that loss of IL1B in AR-positive castration-resistant prostate cancer cells can increase and maintain AR activity in the absence of androgens, suggesting another potential mechanism of high AR activity in castration-resistant prostate cancer.

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Mechanisms of castration resistant prostate cancer formation and progression through neuroendocrine differentiation

10.31083/jomh.2021.040 ◽

2021 ◽

Keyword(s):

Prostate Cancer ◽

Smooth Muscle ◽

Epithelial Cells ◽

Neuroendocrine Differentiation ◽

Underlying Mechanism ◽

Neuroendocrine Cells ◽

Basal Cells ◽

Castration Resistant Prostate Cancer ◽

Normal Prostate ◽

Castration Resistant

Normal prostate tissues consist mainly of epithelial cells, including secretory epithelial cells, basal cells, and neuroendocrine cells, and of mesenchymal cells, including smooth muscle cells and ﬁbroblasts. The mechanisms leading to castration resistant prostate cancer (CRPC) are complex and diverse, but most involve neuroendocrine differentiation. In fact, during the development of prostate cancer, some of the tumor cells transform into neuroendocrine-like cells. This transition is a main underlying mechanism of CRPC formation.

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