The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability

• Published in: Cancer cell 2018-11, Vol.34 (5), p.823-839.e7
• Main Authors: Wang, Hai, Tian, Lin, Liu, Jun, Goldstein, Amit, Bado, Igor, Zhang, Weijie, Arenkiel, Benjamin R., Li, Zonghai, Yang, Meng, Du, Shiyu, Zhao, Hong, Rowley, David R., Wong, Stephen T.C., Gugala, Zbigniew, Zhang, Xiang H.-F.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antineoplastic Agents - pharmacology; Arsenic Trioxide - pharmacology; Benzamides - pharmacology; bone metastasis; Bone Neoplasms - pathology; Bone Neoplasms - prevention & control; Bone Neoplasms - secondary; breast cancer; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Calcium - metabolism; calcium signaling; Calcium Signaling - physiology; Cell Line, Tumor; Cell Proliferation - physiology; Connexin 43 - metabolism; drug discovery or repositioning; Everolimus - pharmacology; Female; gap junctions; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; microenvironment; micrometastasis; Osteogenesis - physiology; prostate cancer; Protein Kinase Inhibitors - pharmacology; Pyrazoles - pharmacology; RAW 264.7 Cells; the osteogenic niche; therapeutic responses; Tumor Microenvironment - physiology; U937 Cells
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2018.10.002

The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs. [Display omitted] •Calcium signaling is enhanced in bone metastasis compared with other metastases•Cancer cells rely on direct calcium influx from osteogenic cells to increase [Ca2+]•Gap junctions mediate Ca2+ flow from osteogenic cells to cancer cells•As2O3 suppresses latent bone metastasis by inhibiting calcium signaling Wang et al. report that cancer cells obtain calcium from the osteogenic niche through gap junctions and that Ca signaling together with mTOR signaling promotes bone metastasis progression. They identify that As2O3 and danusertib affect Ca signaling and preferentially target cancer cells in the bone microenvironment.