Microvesicles and Migratory Heterogeneity in Breast Cancer Progression

Abstract

Intratumor heterogeneity is an emerging hallmark of cancer that complicates diagnostics and therapeutics. Breast tumors are made up of a dynamic extracellular matrix and a heterogeneous collection of cancer and stromal cells. The implications of intratumor heterogeneity on cancer progression are poorly understood. Here, we investigate how heterogeneity in matrix stiffness, migration, and metabolism influence cancer progression. Microvesicles (MVs), a subset of extracellular vesicles released from the plasma membrane of cells, can transfer biologically active cargo to induce a functional change in recipient cells. Breast cancer MVs can induce fibroblast differentiation into a cancer-supporting state; however, it is unclear how matrix stiffness affects this process. Our results indicate that MV-induced fibroblast activation is dependent upon matrix stiffness and is more robust at stiffness mimicking tumorigenic tissue compared to healthy tissue. We next investigate MV-fibroblast signaling in weakly migratory cancer cell dissemination and metastasis. While metastatic cancer cells can be weakly migratory, it is unclear how these cells escape the primary tumor. Our findings reveal that weakly migratory cells release MVs rich in Tg2 which activate fibroblasts to lead cancer cell migration. These MVs also enhance the metastasis of weakly migratory cancer cells. These findings identify Tg2 as a potential therapeutic target and reveal a novel aspect of the metastatic cascade in which weakly migratory cancer cells utilize MV-fibroblast signaling to enhance cancer cell dissemination. Lastly, we investigate how cancer cell metabolism and EMT status regulate migration. Our findings indicate that highly migratory cells primarily utilize glycolysis while weakly migratory cells primarily utilize oxidative phosphorylation. These migratory and metabolic phenotypes are plastic and can be changed by modulation of glucose metabolism or EMT. Identifying mechanisms that fuel phenotypic heterogeneity in breast cancer is essential to develop targeted metastatic therapeutics. The findings in this dissertation elucidate the mechanisms by which intratumor heterogeneity contributes to breast cancer progression. Matrix stiffness, MV signaling, and metabolic heterogeneity may be leveraged to identify future therapeutic targets to prevent cancer metastasis.