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

Abstract

Summary Breast 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 further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets 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. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases.

Distinctive properties of metastasis-initiating cells

“…Recently, the osteogenic niche in bone has been proposed to induce mTOR signaling in DTCs via heterotypic adherens junctions and promote the initial outgrowth of micrometastases in bone ( Fig. 4C; Wang et al 2015b). To successfully form macrometastasis, cancer cells express VCAM1 to recruit preosteoclasts and stimulate osteoclast differentiation, leading to the eventual formation of a "vicious cycle" of metastatic tumor growth, osteoclast-mediated bone lysis, and the release of tumor-promoting growth factors ( Fig.…”

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

“…In vivo models of BoM have unfortunately been somewhat restricted to ER-negative disease due to the more indolent characteristics of ER-positive cell lines (5). Molecular characteristics of ER-positive specimens that have recurred in an estrogen-blunted system, which represents the major burden of breast cancer BoM, are thus essential to reinforce the significant scientific contributions made using in vivo bone metastasis models (6)(7)(8)(9). Nonetheless, data sets are currently limited, in part due to the practical difficulties of obtaining and processing human BoM specimens (10).…”

The endocrine influence on the bone microenvironment in early breast cancer

“…These DTCs are thought to be subject to the same Ob-derived signals that maintain HSC dormancy, thus maintaining tumour cell survival and contributing to relapse in bone many years after the initial diagnosis of the primary tumour. A recent study in mice has demonstrated that breast cancer cells form heterotypic adherence junctions with osteoblastic cells, resulting in activation of mTOR in the tumour cells and their proliferation to form micrometastases, implicating the osteoblasts in early progression (Wang et al 2015).…”