title: SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition.
abstract: 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.
  
  
  
  To understand how NEPC develops and to identify driver genes to inform therapy for NEPC prevention.
  
  
  
  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.
  
  
  
  A novel bioinformatics tool, comparative alternative splicing detection (COMPAS), was invented to analyze alternative RNA splicing on RNA-sequencing data.
  
  
  
  COMPAS identified potential driver genes for NEPC development. Biochemical and biological validations were performed in both prostate cell and tumor models.
  
  
  
  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.
  
  
  
  SRRM4 drives NEPC progression. This knowledge may guide the development of novel therapeutics aimed at NEPC.
  
  
  
  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.
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; School of Computing Science, Simon Fraser University, Burnaby, Canada.
authors.forename: Nilgun
authors.initials: N
authors.lastname: Donmez
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; School of Computing Science, Simon Fraser University, Burnaby, Canada.
authors.forename: Cenk
authors.initials: C
authors.lastname: Sahinalp
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Xie
authors.affiliation: Department of Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Fan
authors.initials: F
authors.lastname: Mo
authors.affiliation: Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; Department of Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; School of Computing Science, Simon Fraser University, Burnaby, Canada; Laboratory for Advanced Genome Analysis, Vancouver, Canada. Electronic address: ccollins@prostatecentre.com.
authors.forename: Colin
authors.initials: C
authors.lastname: Collins
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. Electronic address: xdong@prostatecentre.com.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Dong
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D017398:Alternative Splicing; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D055099:Neuroendocrine Cells / Q000502:physiology; D018358:Neuroendocrine Tumors / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D009419:Nerve Tissue Proteins; D011944:Receptors, Androgen; C000595377:SRRM4 protein, human
keywords: AR inhibition; Alternative RNA splicing; Neuroendocrine prostate cancer; SRRM4