The Osteogenic Niche Promotes Early-Stage Bone Colonization of Disseminated Breast Cancer Cells

• Intrailiac artery injection allows studies of bone metastasis initiation
• Bone micrometastases reside in the microenvironment niche with active osteogenesis
• The niche cells boost tumor proliferation via adherens junctions (AJs)
• The mTOR pathway lies downstream of AJs and mediates metastasis initiation

SummaryBreast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human data set analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases.

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