| dc.description.abstract | The tumor microenvironment is a dynamic system of cellular and extracellular components that vary in composition and interactions within and across patients. This work particularly explores the extracellular matrix (ECM) and cellular heterogeneity observed within the tumor microenvironment (TME) to understand their roles in cancer progression. The first study characterizes aligned collagen matrices, which are a key feature of the TME. This work reveals that collagen alignment in vitro can modify pore sizes and micro-scale stiffness. Therefore, further studies investigating the effects of collagen alignment on cellular behavior must recognize and account for these confounding variables in experimental matrix alignment systems. The second study utilizes single-cell RNA sequencing to assess the effects of ECM stiffening on tumor composition and heterogeneity in mouse mammary tumors. This work uncovered differences in intercellular communication and an increased abundance of pro-tumor M2-like macrophages in stiffer tumors, highlighting a novel mechanism by which matrix stiffness may contribute to tumor progression. Additionally, the third study investigates how ECM stiffening influences endothelial epigenetics, particularly focusing on DNA methylation. This work suggests that stiffer substrates induce lower levels of DNA methylation in endothelial cells, suggesting substrate mechanics may regulate tumor vasculature via epigenetic changes. Lastly, the thesis examines transcriptional profiles across highly migratory and weakly migratory cancer cell subpopulations. Despite minimal common gene expression patterns, significant enrichment of shared biological processes suggests that diverse cancer types may utilize unique pathways for similar biological functions. Collectively, these studies demonstrate the impact of mechanical and behavioral heterogeneities observed in the TME and underscore the necessity of precision medicine approaches. | |
