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

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 7

Cluster analysis using AR, NE, and squamous gene expression profiles segregates mCRPC specimens and LuCaP PDX models into the different phenotypes.

Options: View larger image (or click on image) Download as PowerPoint
Cluster analysis using AR, NE, and squamous gene expression profiles seg...
(A) RNA sequencing of mCRPC specimens acquired between 2003–2017 (n = 98; modified from Figure 1B). NE genes listed in the NEURO I and NEURO II panels, AR and AR-regulated genes are listed in the AR panel, and squamous associated genes are shown in SQUAM panel. Results are expressed as log2 FPKM and colored according to scale. Multidimensional scaling and cluster analysis of (B) mCRPC specimens (n = 98) and (C) LuCaP PDX models using the 26-gene set depicted in A. The LuCaP analysis was conducted on 18 distinct PDX lines (n = 2 for each line). ARPC (AR+/NE–; green), ARLPC (ARlow/NE–; purple), DNPC (AR–/NE–; blue), AMPC/mixed (AR+/NE+; red), SCNPC (AR–/NE+; yellow).