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

Cancer Cell. 2018 Nov 12;34(5):823-839.e7. 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.

Keywords: bone metastasis; breast cancer; calcium signaling; drug discovery or repositioning; gap junctions; microenvironment; micrometastasis; prostate cancer; the osteogenic niche; therapeutic responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Arsenic Trioxide / pharmacology*
  • Benzamides / pharmacology*
  • Bone Neoplasms / pathology*
  • Bone Neoplasms / prevention & control
  • Bone Neoplasms / secondary*
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / therapy
  • Calcium / metabolism
  • Calcium Signaling / physiology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Connexin 43 / metabolism
  • Everolimus / pharmacology
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Osteogenesis / physiology*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology*
  • RAW 264.7 Cells
  • Tumor Microenvironment / physiology
  • U937 Cells


  • Antineoplastic Agents
  • Benzamides
  • Connexin 43
  • GJA1 protein, human
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Everolimus
  • danusertib
  • Arsenic Trioxide
  • Calcium