Elevated collagen I and fibronectin in the ovarian cancer pre-metastatic niche - High-grade serous ovarian cancer (HGSOC) has a five-year survival rate of <50% due to the rapid and extensive metastasis observed in patients. Metastasis in HGSOC can occur through transcoelomic spread, in which tumor cells detach, float through the peritoneal fluid, attach to the peritoneal cavity-facing surfaces of tissues, and establish new tumors. Rapid metastasis is supported when the primary tumor sends signals that convert healthy tissues to a site that is more hospitable for metastasizing tumor cells; the altered tissue is called a premetastatic niche (PMN). Determining what is different in the PMN, how this difference supports metastasis, and the mechanisms responsible for these alterations could lead to therapeutic approaches that slow or stop metastasis. The most common site of distal metastasis in HGSOC is the omentum, a visceral fat deposit. We examined the omentum from healthy females and patients with early-stage HGSOC (prior to metastasis to the omentum). Our preliminary data demonstrated that collagen type I (Col I) density, cellular fibronectin (cFN) density, transglutaminase-2 (TGM2) cross-links, and collagen fiber thickness were all significantly increased in the omentum of patients with early-stage HGSOC. We hypothesize that these changes in the ECM of the omentum result in a PMN that supports tumor progression through direct effects on tumor cell adhesion, invasion, migration, proliferation, and apoptosis, and that the observed ECM changes result from preconditioning of this niche by factors in the peritoneal fluid. We will test this hypothesis across three Aims: 1) Examine the direct effect of ECM alterations observed in the HGSOC PMN on tumor cells. 2) Determine the impact of ECM alterations in the PMN on HSGOC metastatic seeding and expansion. 3) Elucidate mechanisms by which the ECM of the omentum is converted to that of the PMN. These studies will be conducted by an inter-disciplinary team with expertise in ovarian cancer from basic science and clinical perspectives, in vitro culture system development, in vivo mouse models, ECM, biomaterials, and exosomes. Completion of these Aims will determine how changes in the ECM that precede tumor cell arrival influence metastasis. Additionally, we will determine which factors in the peritoneal fluid regulate these changes in the ECM to identify future therapeutic strategies or biomarkers for patients at high risk.
