Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

The Journal of Clinical Investigation
Mark P LabrecqueColm M Morrissey

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole genome RNA sequencing, gene set enrichment analysis and immunohistochemistry. Our analyses revealed five mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: (i) AR-high tumors (ARPC), (ii) AR-low tumors (ARLPC), (iii) amphicrine tumors composed of cells co-expressing AR and NE genes (AMPC), (iv) double-negative tumors (i.e. AR-/NE-; DNPC) and (v) tumors with small cell or NE gene expression without AR activity (SCNPC). RE1-silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the five mCRPC phenotypes. Together, ...Continue Reading

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Apr 3, 2020·The Journal of Experimental Medicine·Grinu Mathew, Lloyd C Trotman
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Datasets Mentioned

BETA
GSE126078

Methods Mentioned

BETA
RNA-Seq
xenograft
biopsy
PCR
laser
MDS
biopsies
transfections
Fluorescence
electrophoresis

Software Mentioned

GSEA
GOrilla
GenomicAlignments Bioconductor
edgeR Bioconductor package
GraphPad Prism
R
TopHat
Gene Set Enrichment Analysis ( GSEA )
GSVA

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