Osteoblast-secreted factors mediate dormancy of metastatic prostate cancer in the bone via activation of the TGF{beta}RIII-p38MAPK-pS249/T252RB pathway

Bone metastasis from prostate cancer (PCa) can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTC are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 PCa cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single cell level revealed that conditioned medium from differentiated, but not undifferentiated osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to PCa cells. Gene array analyses identified GDF10 and TGFβ2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating PCa tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates RB at the novel N-terminal S249/T252 sites to block PCa cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 PCa cell lines abolished tumor cell dormancy both in vitro and in vivo. Lower TGFβRIII expression in PCa patients correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTC are induced into a dormant state through TGFβRIII-p38MAPK-pS249/pT252-RB signaling and offer a rationale for developing strategies to prevent PCa recurrence in the bone.

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