Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer
Mark P. Labrecque, … , Peter S. Nelson, Colm Morrissey
Mark P. Labrecque, … , Peter S. Nelson, Colm Morrissey
Published July 30, 2019
Citation Information: J Clin Invest. 2019;129(10):4492-4505. https://doi.org/10.1172/JCI128212.
View: Text | PDF
Research Article Cell biology Oncology Article has an altmetric score of 12

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

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 5 mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: AR-high tumors (ARPC), AR-low tumors (ARLPC), amphicrine tumors composed of cells coexpressing AR and NE genes (AMPC), double-negative tumors (i.e., AR–/NE–; DNPC), and 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 5 mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.

Authors

Mark P. Labrecque, Ilsa M. Coleman, Lisha G. Brown, Lawrence D. True, Lori Kollath, Bryce Lakely, Holly M. Nguyen, Yu C. Yang, Rui M. Gil da Costa, Arja Kaipainen, Roger Coleman, Celestia S. Higano, Evan Y. Yu, Heather H. Cheng, Elahe A. Mostaghel, Bruce Montgomery, Michael T. Schweizer, Andrew C. Hsieh, Daniel W. Lin, Eva Corey, Peter S. Nelson, Colm Morrissey

×

Figure 4

REST knockdown in AR-expressing and AR-null CRPC cell lines.

Options: View larger image (or click on image) Download as PowerPoint
REST knockdown in AR-expressing and AR-null CRPC cell lines. (A) Immunob...
(A) Immunoblot of REST, AR, SYP, and ACTB using C4-2B, PC-3, and PacMet AR-null cells transfected with either REST siRNA (siREST) or negative control siRNA (siNCT). (B) AR activity scores assessed in C4-2B cells transfected with siNCT (n = 2) or siREST (n = 2) by RNA-Seq. (C) RNA-Seq heatmap of the 24 common upregulated genes (up >3-fold; P < 0.05) between C4-2B, PC-3, and PacMet AR-null cells transfected with siREST or siNCT. Log2 mean-centered ratios of genes are depicted and colored according to scale. (D) Venn diagram describing the interrelationships of all upregulated genes (vs. siNCT; up >3-fold; P < 0.05) identified through RNA-Seq in siREST transfected cell lines.