Title: Mechanics for Inflammatory Cytokine-Promoted Breast Cancer Progression: OSM-Induced Loxl2 Leads to Extracellular Matrix Remodeling of Collagen I and Subsequent Metastasis
Program: Doctor of Philosophy in Biomolecular Sciences
Advisor: Dr. Cheryl Jorcyk, Biological Sciences
Committee Members: Dr. Julia Oxford, Biological Sciences, Dr. Daniel Fologea, Physics, and Dr. Richard Beard, Biological Sciences
Breast cancer has the highest prevalence of cancers in women in the USA; approximately 1 in 8 women will receive a diagnosis in their lifetime. Invasive ductal carcinoma (IDC) is the most commonly diagnosed breast cancer and presents a serious problem if it metastasizes, decreasing 5-year patient survival from ~98% to ~29%. Tumor cells grow in an environment that is known as the tumor microenvironment (TME). Due to inflammation, the TME of IDC is often saturated with neutrophil- and macrophage-derived proinflammatory cytokines including oncostatin M (OSM) and interleukin-1beta (IL-1β), both of which promote favorable conditions for metastasis. Modifications in the organization, density, and alignment of collagen I fibers present in extracellular matrix (ECM) of the TME directly impact IDC cell motility and invasiveness, both factors in metastasis. Lysyl oxidase like-2 (LOXL2) is an enzymatic protein secreted by fibroblast and IDC cells that catalyzes the crosslinking of collagen I fibers in the ECM. Increased collagen crosslinking alters the characteristics mentioned above, worsening patient prognosis and promoting metastasis. Proposed is a novel mechanism for proinflammatory cytokine-promoted ECM remodeling and subsequent metastasis in IDC. OSM signaling induces enzymatically active LOXL2 expression and extracellular secretion, leading to significant remodeling of ECM collagen I fibers that promotes significantly increased invasion, tumor growth, and metastasis. LOXL2-mediated ECM remodeling is also critical for OSM promoted IDC tumor growth and metastatic progression. Combined, these results demonstrate that OSM-induced LOXL2 has serious implications for IDC tumor progression and metastasis.