Calcium signaling and mTOR signaling drive bone metastasis progression.

  • Major finding: Calcium signaling and mTOR signaling drive bone metastasis progression.

  • Mechanism: Gap junctions facilitate calcium transfer from osteogenic cells to tumor cells.

  • Impact: Inhibiting calcium signaling with As2O3 in combination with mTOR inhibition may suppress bone metastasis.

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The bone is the site most frequently colonized by breast cancer metastases, and these metastases are driven by a well-characterized vicious cycle between cancer cells and osteoclasts. However, early-stage bone colonization, before the onset of the vicious cycle, is incompletely understood. Heterotypic adherens junctions form between cancer cells and osteogenic cells, activating mTOR signaling to promote the progression of bone micrometastases, but mTOR inhibitors failed to extend survival. Wang and colleagues sought to identify additional pathways that may cooperate with mTOR signaling to mediate the metastasis-promoting effects of the osteogenic niche. Calcium signaling was increased in bone metastases compared with metastases in other organs. The transcription factors NFAT and MEF2, both of which are downstream of calcium signaling, were also upregulated in bone metastases. In vivo, NFAT1 and MEF2 activity was increased in a mouse model of bone metastasis. Further, coculturing tumor cells with osteogenic cells enhanced tumor-cell proliferation and increased nuclear NFAT, indicating that the interaction with osteogenic cells drives the increase in calcium signaling in tumor cells. Conversely, inhibiting calcium signaling reduced bone colonization of tumor cells. Mechanistically, calcium was delivered from osteogenic cells to tumor cells via gap junctions to promote bone colonization. Connexin 43 (Cx43) is a major component of gap junctions and was overexpressed in bone metastases and associated with calcium signaling. Inhibiting Cx43 suppressed bone colonization, but also had significant side effects in mice. A bone-in-culture array screen identified arsenic trioxide (As2O3) as a suppressor of bone metastasis that disrupted calcium signaling and gap junctions with fewer side effects in vivo. As2O3 combined with mTOR inhibition reduced latent bone recurrence in a mouse model of ER+ breast cancer. Collectively, these findings reveal a mechanism by which calcium signaling promotes bone metastases and suggest the potential for As2O3 in combination with mTOR inhibition to eliminate bone metastases.

Wang H, Tian L, Liu J, Goldstein A, Bado I, Zhang W, et al. The osteogenic niche is a calcium reservoir of bone micrometastases and confers unexpected therapeutic vulnerability. Cancer Cell 2018;34:823–39.e7.

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