A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance
Menée à l'aide d'un modèle murin de cancer de la prostate avec métastases osseuses et à l'aide de données transcriptomiques portant sur des échantillons tumoraux d'origine humaine et des échantillons tumoraux d'origine murine, cette étude met en évidence une association entre une signature, basée sur l'expression de gènes impliqués dans la co-activation de MYC et RAS, et le développement de métastases osseuses ainsi que la résistance des cellules cancéreuses à la castration thérapeutique
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.
Nature Cancer , résumé, 2020