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Updated: Mar 21, 2026
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway
Yinan Li1, Nilgun Donmez2, Cenk Sahinalp2
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Background:
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castration-resistant prostate cancer that typically does not respond to androgen receptor pathway inhibition (ARPI), and its diagnosis is increasing.
Objective:
To understand how NEPC develops and to identify driver genes to inform therapy for NEPC prevention.
Design, Setting, And Participants:
Whole-transcriptome sequencing data were extracted from prostate tumors from two independent cohorts: The Beltran cohort contained 27 adenocarcinoma and five NEPC patient samples, and the Vancouver Prostate Centre cohort contained three patient samples and nine patient-derived xenografts.
Intervention:
A novel bioinformatics tool, comparative alternative splicing detection (COMPAS), was invented to analyze alternative RNA splicing on RNA-sequencing data.
Outcome Measurements And Statistical Analysis:
COMPAS identified potential driver genes for NEPC development. Biochemical and biological validations were performed in both prostate cell and tumor models.
Results And Limitation:
More than 66% of the splice events were predicted to be regulated by the RNA splicing factor serine/arginine repetitive matrix 4 (SRRM4). In vitro and in vivo evidence confirmed that one SRRM4 target gene was the RE1 silencing transcription factor (REST), a master regulator of neurogenesis. Moreover, SRRM4 strongly stimulated adenocarcinoma cells to express NEPC biomarkers, and this effect was exacerbated by ARPI. ARPI combined with a gain of SRRM4-induced adenocarcinoma cells to assume multicellular spheroid morphology and was essential in establishing progressive NEPC xenografts. These SRRM4 actions were further enhanced by loss of function of TP53.
Conclusions:
SRRM4 drives NEPC progression. This knowledge may guide the development of novel therapeutics aimed at NEPC.
Patient Summary:
Using next-generation RNA sequencing and our newly developed bioinformatics tool, we identified a neuroendocrine prostate cancer (NEPC)-specific RNA splicing signature that is predominantly controlled by serine/arginine repetitive matrix 4 (SRRM4). We confirmed that SRRM4 drives NEPC progression, and we propose SRRM4 as a potential therapeutic target for NEPC.
Insights
Serine/arginine repetitive matrix 4 (SRRM4) drives neuroendocrine prostate cancer (NEPC) progression. Targeting SRRM4 may offer new therapeutic strategies for this aggressive cancer subtype.
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castration-resistant prostate cancer.
- NEPC often shows resistance to androgen receptor pathway inhibition (ARPI).
- The incidence of NEPC diagnoses is increasing globally.
Purpose of the Study:
- To elucidate the molecular mechanisms driving NEPC development.
- To identify key driver genes for NEPC.
- To inform the development of novel NEPC therapies.
Main Methods:
- Whole-transcriptome sequencing of prostate tumor samples from two independent cohorts.
- Development and application of a novel bioinformatics tool, comparative alternative splicing detection (COMPAS).
- In vitro and in vivo validation of identified genes and pathways.
Main Results:
- A NEPC-specific RNA splicing signature was identified, predominantly regulated by serine/arginine repetitive matrix 4 (SRRM4).
- SRRM4 was confirmed to drive NEPC progression, stimulating NEPC biomarker expression in adenocarcinoma cells.
- SRRM4's effects were exacerbated by ARPI and TP53 loss of function, promoting aggressive tumor phenotypes.
Conclusions:
- SRRM4 is a critical driver of NEPC progression.
- SRRM4 represents a potential therapeutic target for NEPC.
- Understanding SRRM4's role may guide the development of novel NEPC treatments.
