Dormancy of disseminated prostate cancer cells in the bone cortex is induced by osteoblasts

Abstract

AbstractPrimary prostate cancer (PCa) cells can disseminate early and stay dormant in distant organs but reactivate later, causing lethal metastasis and recurrence, but the mechanisms of PCa dissemination and dormancy remain elusive. Using C4-2B PCa subcutaneous xenograft mouse model, we observed that the disseminated tumor cells (DTC) were enriched in the bones after tumor removal, more specifically, in the bone cortex. We hypothesized that DTC are dormant in the bone cortex and determined osteoblasts as the inducer for PCa dormancy via an in vitro mixed co-culture model. Through RNA-sequencing we defined a unique PCa dormancy gene signature with significantly decreased mitochondrial gene expressions and mitochondria-related functions, which was positively associated with clinical PCa progression. We further predicted dormancy-mimicking drugs using a novel artificial intelligence (AI) platform and validated PF-562271, a focal adhesion kinase (FAK) inhibitor, as dormancy-mimicking in vitro. Altogether, our study revealed for the first time the effects of primary tumor removal on PCa cell dissemination, profiled the osteoblasts-induced C4-2B cell dormancy, and induced PCa cell dormancy in vitro using AI predicted drugs, which could potentially inhibit PCa bone metastasis progression and recurrence clinically.