Abstract BS1-3: New insights into early-stage bone colonization of disseminated breast cancer cells

Abstract

The fate of disseminated tumor cells is heavily influenced by their microenvironment niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using a variety of pre-clinical models and bioinformatics analyses of clinical data. We find that disseminated tumor cells may follow a “migration-by-tethering” mechanism to reach the osteogenic niche and establish tight direct interaction with the osteogenic cells. This interaction in turn profoundly alters signaling cascades in bone micrometastases. Heterotypic adherens junctions between cancer cells and osteogenic cells induce activation of the mTOR signaling. Gap junctions mediate calcium flux from osteogenic cells to cancer cells, and activate the calcium signaling. Upon the development of these junctions, ER signaling in ER+ breast cancer cells is dramatically suppressed, conferring endocrine independence. These alterations lead to unexpected therapeutic resistance and sensitivity, which were elucidated in part by a novel ex vivo bone-in-culture array system. Our findings, together with others in the literature, demonstrate the importance of considering microenvironment effects in metastatic therapies, and suggest novel therapeutic strategies to eliminate micrometastases. Citation Format: Zhang X. New insights into early-stage bone colonization of disseminated breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr BS1-3.