Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGFβRIII–p38MAPK–pS249/T252RB Pathway

Abstract

Bone metastasis from prostate cancer can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTCs 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 prostate cancer 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 prostate cancer 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 prostate cancer tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates retinoblastoma (RB) at the novel N-terminal S249/T252 sites to block prostate cancer cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 prostate cancer cell lines abolished tumor cell dormancy both and Lower TGFβRIII expression in patients with prostate cancer correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTCs are induced into a dormant state through TGFβRIII-p38MAPK-pS249/pT252-RB signaling and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. These findings provide mechanistic insights into the dormancy of metastatic prostate cancer in the bone and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. .

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

“…To do this, we first explored the phenotypic consequences of p38/MAPK pathway activation. The p38/MAPK pathway is a key regulator of the stress response (Igea and Nebreda, 2015), and a regulator of tumor cell dormancy in many cancer types, including prostate cancer (Decker et al, 2017; Yu-Lee et al, 2018). Consistent with the role of p38 in a dormancy phenotype, enzaR cells exhibited a significant downregulation in the ratios of pERK:p38α, an important indicator of the shift from a proliferative (high ERK) to dormant (high p38α) phenotype ( Supplemental Fig S7A ).…”

Bone as a Preferential Site for Metastasis

“…Microenvironmental factors known to regulate HSC quiescence include bone morphogenetic proteins (BMPs), TGFβ2, and growth arrest‐specific protein 6 (GAS6), which were among the first factors identified to induce dormancy of prostate cancer cells and head and neck squamous cell carcinoma. These secreted factors as well as other molecular signals, including retinoic acid and urokinase plasminogen activator receptor (uPAR), have been shown to alter the ratio of ERK and p38 MAPK signaling, which has become one of the most well‐established mechanisms for inducing tumor cell dormancy . Specifically, preferential activation of p38 MAPK over ERK signaling (p38 high / ERK low ) results in the induction of DTC dormancy.…”

“…A combination of Src and ERK inhibition has been shown to effectively reduce breast cancer metastasis to the lungs . Given the known roles of Src and ERK signaling in promoting dormancy escape of tumor cells in the bone, this combination treatment may be an effective treatment to maintain tumor cells in a dormant state and prevent recurrence. Given the newly identified role of epigenetics in regulating tumor dormancy, epigenetic‐modulating therapies may also represent promising therapeutic options to induce dormancy in DTCs.…”

Mechanical Forces as Determinants of Disseminated Metastatic Cell Fate

“…TGFβ2 has been consistently reported as dormancy inducer. Inhibition of TGF-β receptors induces multi-organ outgrowth of disseminated HNSCC [110], proliferation of dormant prostate cancer cells in an in vitro model of dormancy in the bone marrow [111] and poor survival rate in prostate cancer patients [112]. Importantly, TGFβ2 expression was found to be high in single cells isolated from bone marrow of patients with dormant disease, while it dropped in patients with advanced disease.…”