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.
Bibliographical noteFunding Information:
We are grateful to D. Adams for assistance with the initial WES and E. Davicioni and T. Lotan for sharing clinical cohorts. We thank A. Aytes, R. Dalla-Favera, G. Karsenty and M. Shen for comments on the manuscript. This research was funded in part through the National Institutes of Health (NIH)/NCI Cancer Center Support Grant P30CA013696, which supported the Molecular Pathology, Flow Cytometry, Genomics and High Throughput Screening and Oncology Precision Therapeutics and Imaging Cores. The research was supported by NIH grants R01 CA193442, R01 CA173481 and R01 CA183929 (to C.A.S.), P50 CA211024 (to M.A.R.), U54CA209997 (to P.A.S. and C.A.S.), P50 CA097186 (to P.S.N.) and DOD grant W81XWH-17-1-0415 (to P.S.N.). P.S.N. was supported by Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award (SU2C-AACR-DT0712). A.M. was supported by start-up funds from Rutgers School of Health Professions. J.M.A. was supported by a postdoctoral training grant from the Department of Defense Prostate Cancer Research Program (W81XWH-15-1-0185), an Irving Institute/Clinical Trials Office Pilot Award funded by the National Center for Advancing Translational Sciences, NIH (UL1TR001873) and the Dean’s Precision Medicine Research Fellowship from the Irving Institute for Clinical and Translational Research at CUIMC (UL1TR001873). S.P. was supported by New Jersey Commission on Cancer Research Pre-Doctoral Fellowship (DCHS20PPC028). M.Z. was supported by the National Center for Advancing Translational Sciences, NIH, grant number UL1TR001873. A.G. is a recipient of a Prostate Cancer Foundation Young Investigator Award. C.J.M. was supported by NIH fellowship F31CA210607. C.A.S. is supported by the TJ Martell Foundation for Leukemia, Cancer and AIDS Research and the Prostate Cancer Foundation and is an American Cancer Society Research Professor.
A.M.D. has sponsored research funding from Janssen R&D and consults for Cepheid. R.J.K. receives Royalties from GenomeDx. E.S.A. has served as a paid consultant/advisor to Janssen, Pfizer, Sanofi, Dendreon, Bayer, Bristol Myers Squibb, Amgen, Merck, AstraZeneca and Clovis; has received research grants to his institution from Janssen, Johnson&Johnson, Sanofi, Bristol Myers Squibb, Pfizer, AstraZeneca, Celgene, Merck, Bayer and Clovis; and is an inventor of a biomarker technology that has been licensed to QIAGEN. All other authors declare no competing interests.
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