A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance

Juan M. Arriaga, Sukanya Panja, Mohammed Alshalalfa, Junfei Zhao, Min Zou, Arianna Giacobbe, Chioma J. Madubata, Jaime Yeji Kim, Antonio Rodriguez, Ilsa Coleman, Renu K. Virk, Hanina Hibshoosh, Onur Ertunc, Büşra Ozbek, Julia Fountain, R. Jeffrey Karnes, Jun Luo, Emmanuel S. Antonarakis, Peter S. Nelson, Felix Y. FengMark A. Rubin, Angelo M. De Marzo, Raul Rabadan, Peter A. Sims, Antonina Mitrofanova, Cory Abate-Shen

Research output: Contribution to journalArticlepeer-review

Abstract

Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPKEYFP mice (for Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-G12D/+; R26R-CAG-LSL-EYFP/+) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Transcriptomic and whole-exome analyses of bone metastasis from these mice revealed distinct molecular profiles conserved between human and mouse and specific patterns of subclonal branching from the primary tumor. Integrating bulk and single-cell transcriptomic data from mouse and human datasets with functional studies in vivo unravels a unique MYC/RAS co-activation signature associated with prostate cancer metastasis. Finally, we identify a gene signature with prognostic value for time to metastasis and predictive of treatment response in human patients undergoing androgen receptor therapy across clinical cohorts, thus uncovering conserved mechanisms of metastasis with potential translational significance.

Original languageEnglish (US)
Pages (from-to)1082-1096
Number of pages15
JournalNature Cancer
Volume1
Issue number11
DOIs
StatePublished - Nov 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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