RNA splicing factors SRRM3 and SRRM4 distinguish molecular phenotypes of castration-resistant neuroendocrine prostate cancer

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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The Androgen Receptor Complexes with RNA Splicing Factors – Implications in Prostate Cancer Progression.

10.1210/endo-meetings.2010.part2.p1.p2-1 ◽

2010 ◽

pp. P2-1-P2-1

Author(s):

M Paliouras ◽

R Lumbroso ◽

L Kapogeorgakis ◽

M Trifiro

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Progression ◽

Rna Splicing ◽

Splicing Factors ◽

Prostate Cancer Progression ◽

Receptor Complexes

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Preclinical studies using cisplatin/carboplatin to restore the Enzalutamide sensitivity via degrading the androgen receptor splicing variant 7 (ARv7) to further suppress Enzalutamide resistant prostate cancer

Cell Death and Disease ◽

10.1038/s41419-020-02970-4 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Fu-Ju Chou ◽

ChangYi Lin ◽

Hao Tian ◽

WanYing Lin ◽

Bosen You ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Rna Splicing ◽

Preclinical Studies ◽

Castration Resistant Prostate Cancer ◽

Splicing Variant ◽

Castration Resistant ◽

Lncrna Malat1 ◽

Near Future

Abstract The FDA-approved anti-androgen Enzalutamide (Enz) has been used successfully as the last line therapy to extend castration-resistant prostate cancer (CRPC) patients’ survival by an extra 4.8 months. However, CRPC patients eventually develop Enz-resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we found that Cisplatin (Cis) or Carboplatin, currently used in chemotherapy/radiation therapy to suppress tumor progression, could restore the Enz sensitivity in multiple Enz-resistant (EnzR) CRPC cells via directly degrading/suppressing the ARv7. Combining Cis or Carboplatin with Enz therapy can also delay the development of Enz-resistance in CRPC C4-2 cells. Mechanism dissection found that Cis or Carboplatin might decrease the ARv7 expression via multiple mechanisms including targeting the lncRNA-Malat1/SF2 RNA splicing complex and increasing ARv7 degradation via altering ubiquitination. Preclinical studies using in vivo mouse model with implanted EnzR1-C4-2 cells also demonstrated that Cis plus Enz therapy resulted in better suppression of EnzR CRPC progression than Enz treatment alone. These results not only unveil the previously unrecognized Cis mechanism to degrade ARv7 via targeting the Malat1/SF2 complex and ubiquitination signals, it may also provide a novel and ready therapy to further suppress the EnzR CRPC progression in the near future.

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RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression

European Urology ◽

10.1016/j.eururo.2019.03.011 ◽

2019 ◽

Vol 76 (2) ◽

pp. 157-166 ◽

Cited By ~ 5

Author(s):

Yinan Li ◽

Ning Xie ◽

Ruiqi Chen ◽

Ahn R. Lee ◽

Jessica Lovnicki ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Rna Splicing ◽

Prostate Cancer Progression ◽

Neuroendocrine Prostate Cancer

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Identification of Novel Diagnosis Biomarkers for Therapy-Related Neuroendocrine Prostate Cancer

Pathology & Oncology Research ◽

10.3389/pore.2021.1609968 ◽

2021 ◽

Vol 27 ◽

Author(s):

Cuijian Zhang ◽

Jinqin Qian ◽

Yucai Wu ◽

Zhenpeng Zhu ◽

Wei Yu ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Characteristics ◽

Expression Profiles ◽

Prostate Adenocarcinoma ◽

Diagnostic Tools ◽

Receptor Interaction ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Neuroendocrine Prostate Cancer ◽

Platinum Based Chemotherapy

Background: Therapy-related neuroendocrine prostate cancer (NEPC) is a lethal castration-resistant prostate cancer (CRPC) subtype that, at present, lacks well-characterized molecular biomarkers. The clinical diagnosis of this disease is dependent on biopsy and histological assessment: methods that are experience-based and easily misdiagnosed due to tumor heterogeneity. The development of robust diagnostic tools for NEPC may assist clinicians in making medical decisions on the choice of continuing anti-androgen receptor therapy or switching to platinum-based chemotherapy.Methods: Gene expression profiles and clinical characteristics data of 208 samples of metastatic CRPC, including castration-resistant prostate adenocarcinoma (CRPC-adeno) and castration-resistant neuroendocrine prostate adenocarcinoma (CRPC-NE), were obtained from the prad_su2c_2019 dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was subsequently used to construct a free-scale gene co-expression network to study the interrelationship between the potential modules and clinical features of metastatic prostate adenocarcinoma and to identify hub genes in the modules. Furthermore, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a model to predict the clinical characteristics of CRPC-NE. The findings were then verified in the nepc_wcm_2016 dataset.Results: A total of 51 co-expression modules were successfully constructed using WGCNA, of which three co-expression modules were found to be significantly associated with the neuroendocrine features and the NEPC score. In total, four novel genes, including NPTX1, PCSK1, ASXL3, and TRIM9, were all significantly upregulated in NEPC compared with the adenocarcinoma samples, and these genes were all associated with the neuroactive ligand receptor interaction pathway. Next, the expression levels of these four genes were used to construct an NEPC diagnosis model, which was successfully able to distinguish CRPC-NE from CRPC-adeno samples in both the training and the validation cohorts. Moreover, the values of the area under the receiver operating characteristic (AUC) were 0.995 and 0.833 for the training and validation cohorts, respectively.Conclusion: The present study identified four specific novel biomarkers for therapy-related NEPC, and these biomarkers may serve as an effective tool for the diagnosis of NEPC, thereby meriting further study.

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Extracellular Microenvironment in Patient-derived Hydrogel Organoids of Prostate Cancer Regulates Therapeutic Response

10.1101/2020.05.17.20104349 ◽

2020 ◽

Author(s):

Matthew J Mosquera ◽

Rohan Bareja ◽

Jacob M Bernheim ◽

Muhammad Asad ◽

Cynthia Cheung ◽

...

Keyword(s):

Prostate Cancer ◽

Inflammatory Cells ◽

Cellular Reprogramming ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Prostate Cells ◽

Synthetic Hydrogel ◽

Neuroendocrine Prostate Cancer ◽

Prostate Cancers ◽

Novel Target

Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

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