The Role of Mechanical Cues and Metabolism in Breast Cancer Cell Migration

Abstract

Breast cancer metastasis is initiated when cells break through basement membrane and migrate through the surrounding tissue before spreading throughout the body to colonize secondary sites. The primary tumor microenvironment, composed primarily of collagen, imparts mechanical challenges upon cancer cells that regulate their migration ability, metabolism, and metastatic potential. In this dissertation, I investigate the interplay of confinement and cellular metabolism in breast cancer cell migration using an engineered collagen microtrack platform. Cancer cells migrating through the primary tumor microenvironment must navigate confined spaces in the tissue. Using our collagen microtrack platform, we find that breast cancer cells in confinement exhibit increased velocity and cell-generated matrix strains. Further, cells maintain increased velocity even after transitioning from a confined to an unconfined region, indicating that cells can be conditioned in confinement to alter future migration ability. We find that this priming in confinement correlates with increased mitochondrial localization at the leading edge of the cell, and that disrupting focal adhesion formation by knocking out vinculin inhibits memory and mitochondrial localization. We next investigate the role of glucose metabolism and epithelial-to-mesenchymal transition (EMT) in migration through collagen microtracks. We find that modulating glucose metabolism by inhibiting glycolysis or oxidative phosphorylation can shift EMT status to alter migration ability. Further, inducing EMT can modulate cell metabolism to affect migration ability, indicating a link between cancer cell bioenergetics and EMT. Finally, we establish cellular metabolic phenotype as a stable, heritable trait of cancer cells that can determine cell response to mechanical cues and migration ability. Specifically, higher energy cells with increased ATP:ADP ratios exhibit increased velocity in confinement compared to lower energy cells. Taken together, this work identifies a key link between metabolism and confined migration in breast cancer cells and highlights potential avenues for therapeutics to treat breast cancer metastasis.