Regulation of Ovarian Carcinoma Proteinases

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DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among US women and the major cause of death from gynecologic malignancy, causing >15,500 mortalities/year. Most women are diagnosed with disseminated metastatic disease; as such the mortality rate from EOC has not been reduced appreciably in 30 years. EOC metastasizes via exfoliation of single cells and multicellular aggregates (MCAs) from the primary tumor that survive in suspension, adhere intra-peritoneally (ip), undergo localized invasion into the interstitial collagen-rich sub-mesothelial matrix and proliferate to anchor secondary lesions. The factors that regulate EOC metastatic success and control the transition from free-floating cells to life-threatening peritoneally anchored metastatic lesion are unknown. Studies in the previous funding period highlighted the role of ¿1 integrin-mediated adhesion to ip collagen in expression and function of the membrane-tethered collagenase MT1-MMP (MMP-14). These mechanistic studies generated exciting new data on the function of cytoplasmic tail phosphorylation in regulation of MT1-MMP membrane dynamics, discovered a role for MT1-MMP in MCA formation from cell-cell adherent sheets, identified a panel of gene products involved in metastasis that are regulated by integrin signaling, and demonstrated that E-cadherin dynamics and ¿-catenin-regulated transcription are modulated downstream of integrin engagement. In the current proposal, we will continue to address the hypothesis that a functional link between adhesion and proteolysis regulates ovarian cancer metastasis. Studies in Aim 1 will evaluate how post-translational regulation of the MT1-MMP cytoplasmic tail contributes to metastatic success using a panel of in vitro and in vivo assays with which to mechanistically model key events in EOC ip metastasis. The role of adhesion-mediated integrin linked kinase (ILK) activation in EOC metastasis will be evaluated in Aim 2. Experiments proposed in Aim 3 will examine integrin regulation of ¿-catenin target genes and epithelial/mesenchymal transition. EOC ip dissemination is distinct from that of most other solid tumors that metastasize hematogenously and thereby presents a distinct set of therapeutic challenges. A molecular level understanding of how EOC tumor cells metastasize is necessary for the development of novel therapies to inhibit ip spread and thereby improve the survival of thousands of women with EOC. PUBLIC HEALTH RELEVANCE: Development of models that accurately reflect the metastatic competence of epithelial ovarian cancer (EOC) represents a remarkable scientific challenge, because the EOC metastatic mechanism involves a novel shedding of multi-cellular aggregates (MCAs) into a cavity (peritoneal cavity) as anchorage-independent, chemotherapy-resistant spheroids. In this unique niche, molecular events that occur during the transition from free-floating MCA to life-threatening peritoneally anchored metastatic lesion are poorly understood. Understanding this transition will enable novel means of targeting intraperitoneal therapies to appropriate multicellular populations.