American Association for Cancer Research
00085472can171051-sup-181687_4_supp_4572206_p47hz3.docx (1.66 MB)

Figure S2 from Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGFβRIII–p38MAPK–pS249/T252RB Pathway

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journal contribution
posted on 2023-03-31, 01:21 authored by Li-Yuan Yu-Lee, Guoyu Yu, Yu-Chen Lee, Song-Chang Lin, Jing Pan, Tianhong Pan, Kai-Jie Yu, Bin Liu, Chad J. Creighton, Jaime Rodriguez-Canales, Pamela A. Villalobos, Ignacio I. Wistuba, Eulalia de Nadal, Francesc Posas, Gary E. Gallick, Sue-Hwa Lin

TGFβ2 and GDF10 induce long-term dormancy in C4-2B4 cells.



Cancer Prevention Research Institute of Texas



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 in vitro and in vivo. 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.Significance: 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. Cancer Res; 78(11); 2911–24. ©2018 AACR.