The Sobering Effect of Matrix Alignment on Breast Cancer Cell Migration

Collagen type I is the most abundant protein in human tissues, and plays many roles in both normal and pathological processes. Collagen not only exists as a biochemical ligand, but also serves as a structural scaffold to support cell adhesion and overall tissue architecture. In breast cancer, collagen I is strongly implicated in disease progression due to increased abundance, which is correlated with increased mammographic density and confers an elevated breast cancer risk. Higher levels of collagen are also linked to increased tumor stiffness and a more invasive cell phenotype. In addition to stiffness, collagen organization is altered with tumor progression and results in fibers oriented perpendicular to tumor boundaries. This arrangement appears to promote cell migration out of tumors and leads to increased metastasis. Here we investigated the mechanisms by which migrating cells respond to aligned collagen. By combining approaches to study matrix stiffness and the speed and persistence of migrating cells in both aligned and randomly organized matrices, we found that cells primarily employ a contact-guidance mechanism that enables more directional migration without altering cell speed. Despite the increased stiffness of aligned collagen, stiffness did not appear responsible for the enhanced migration in aligned matrices. These results were further described in a computational model of cell migration and support the presence of aligned collagen as a prognostic signature for breast cancer. Moreover, this thesis describes two different approaches for generating aligned collagen matrices in vitro that can be used to further study cellular responses to changes in matrix organization.