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

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. 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.