Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPK EYFP mice (for Nkx3.1 CreERT2/+ ; Pten flox/flox ; Kras LSL-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.
Nature cancer. 2020 Oct 19 [Epub]
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 Feng, Mark A Rubin, Angelo M De Marzo, Raul Rabadan, Peter A Sims, Antonina Mitrofanova, Cory Abate-Shen
Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA., Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, Newark, NJ, USA., Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA., Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA., Department for BioMedical Research, University of Bern and Inselspital, Bern, Switzerland., Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA., Department of Urology, Mayo Clinic, Rochester, MN, USA., Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, Newark, NJ, USA. ., Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA. .