Tissue Stiffness Drives Breast Cancer Malignant Progression

Breast cancer is the most common cancer of women worldwide and the second leading cause of cancer death in women in the United States. Despite new therapies that show efficacy in treating the primary tumor there is a significant lack of therapies that treat metastasis, the most common cause of death. This deficit underscores the necessity for a new perspective in the study of breast cancer metastasis. Breast cancer malignant progression coincides with drastic tissue extracellular matrix (ECM) remodeling and stiffening. Previous work in our lab has shown that ECM stiffening is both necessary and sufficient to drive tumor aggression and metastasis in vivo. Consistently, our lab has demonstrated ECM mechanical properties act through integrin focal adhesions to regulate cell functions critical to tumor aggression such as cell proliferation, survival, and motility. Yet, how ECM structural changes occur with tumor progression and which signaling mechanisms downstream of cell-ECM adhesions are critical for tumor aggression remains unclear. In this thesis I address the overarching hypothesis that ECM mechanical properties influence tumor malignant progression through integrin focal adhesion signaling and subsequent downstream signaling affecting tumor motility and invasion, tumor metabolism, and immune cell response. To address this hypothesis I used a combination of isolated mammary epithelial cells with 2D and 3D mechanically tunable substrates ex vivo, in vivo breast cancer models, and human breast cancer tissues samples to robustly quantify the physical and structural ECM changes with tumor progression, identify through which integrin signaling mechanisms tumor cells sense these changes, and determine how tumor cell mechanosensing alters cell signaling to regulate tumor metastasis. From this work I found that tumor cell malignant phenotype is enhanced by ECM stiffness specifically via α5β1 – FN integrin binding which enhances pro-tumorigenic cell signaling to enhance tumor cell invasion and migration and alter tumor cell metabolism. Additionally, ECM stiffness alters tumor cytokine secretion and inflammatory signaling to regulate immune system response which I show in both in vivo models and human samples plays a critical role in tumor malignant progression. Thus, this work provides new mechanistic insight into how the physical microenvironment regulates tumor malignant progression