10th Annual Symposium
Physics of Cancer
September 25-27, 2019
|PoC - Physics of Cancer - Annual Symposium|
Organic and inorganic ECM components as synergistic regulators of breast cancer metastasis
Cornell University, Meinig School of Biomedical Engineering, Carpenter Hall 313 Campus Rd. Ithaca, New York 14853,USA
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Breast cancer bone metastasis is associated with poor clinical prognosis and has been attributed to a small population of cancer cells that exhibit therapy resistance and stem cell-like properties (CSCs). Decreased bone mineral density is clinically linked to increased risk of bone metastasis and is associated with impaired collagen mineralization. Whether altered collagen mineralization is a direct regulator of stem cell-like properties and chemotherapy resistance of breast cancer cells, however, remains unclear. Here, we have utilized a biomimetic approach to mineralize collagen fibers in a physiologically relevant, intrafibrillar manner to investigate the functional relationship between collagen mineralization, stem cell-like properties of breast cancer cells, and chemotherapy resistance. A combination of materials characterization approaches confirmed biomimetic mineralization of collagen fibers with intrafibrillar hydroxyapatite crystals. Breast cancer cells cultured on mineralized substrates exhibited reduced adhesion forces and accordingly reduced collagen fiber alignment relative to cells cultured on control collagen. The resulting mineral-mediated changes in collagen network characteristics and mechanosignaling correlated with increased cell motility, but inhibited directed migration of breast cancer cells. Furthermore, tumor cells cultured on mineralized vs. control collagen assumed more stem-like characteristics as detected with Nanog-GFP MDA-MB231 reporter cells and analysis of aldehyde dehydrogenase activity. These results were dependent on the presence of mineral as revealed by a dose response study and were not an artefact of the collagen culture model as studies with decellularized and demineralized native bone yielded similar results. Gene set enrichment analysis of cells cultured on mineralized vs. control collagen suggested that cell cycle-related gene sets were expressed as a function of collagen mineralization. Indeed, tumor cells cultured on control vs. mineralized collagen proliferated more and were more resistant to doxorubicin treatment due to reduced intracellular accumulation of the chemotherapeutic drug. These results suggest that interactions with mineralized collagen can promote stem-like properties of breast cancer cells, which, in turn, are associated with resistance to chemotherapy. This study provides insights into the effect of bone ECM on breast cancer metastasis.