Integrative Analysis of the Aging Peritoneum in Metastatic Receptivity

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The overall goal of this proposal is to provide a comprehensive plan of research training and career development to enable the principal investigator to successfully complete her PhD and acquire a competitive postdoctoral position performing translational research in the fields of aging and cancer. Phase I focuses on completion of ongoing PhD training investigating the role of the aging microenvironment in ovarian cancer (OvCa) metastasis. OvCa is the most fatal gynecologic malignancy and the 5th leading cause of overall cancer death among American women with a low 5-year survival rate, as 75% of women are diagnosed with disseminated intra-peritoneal (IP) metastasis. OvCa metastasis differs from most other cancers in that cells detach from the primary tumor, shed into the peritoneal cavity, adhere to the peritoneal mesothelial cell (MC) monolayer, intercalate within this layer, and invade into the submesothelial matrix, where they proliferate and form secondary lesions. Aging is the biggest risk factor for the development of OvCa. Half of OvCa diagnoses are in women over the age of 63, and older OvCa patients have a higher risk of mortality. Despite this, age is understudied in the OvCa field. Even though the peritoneum has near the same surface area as the skin, the effect of age on the peritoneum has not been systematically evaluated. Using three distinct murine pre-clinical models of aging and OvCa metastasis, our lab previously demonstrated enhanced metastatic seeding of peritoneal structures in aged mice accompanied by altered immune cell infiltration. Current preliminary data in this application show that there are distinct differences observed when comparing peritoneal collagen ultrastructure in young and aged animals at major metastatic sites. Moreover, using purified collagen from young versus aged mice in a panel of in vitro assays, we showed increased invasion of OvCa cells through aged collagen relative to young, despite no difference in adhesion or proliferation. Differential susceptibility to proteolytic remodeling was also observed. This data supports our hypothesis that age-related changes to the metastatic environment enhance ovarian cancer metastasis in aged patients. The Phase I goal of the proposed research is to identify small molecules that can target these age-related structural modifications in collagen with the goal of reducing metastatic dissemination in aged mice. Additional studies will evaluate the other major component of the peritoneal cavity, the visceral adipocytes, with characterization of age-related changes in the adipocytes proteome. The Phase II goal will focus on the immune landscape of an aging cancer. Studies will focus on T cell infiltration and immunosenescence with aging. The emphasis on multi-disciplinary aspects of aging throughout the training, combining a predoctoral focus on the tumor metastatic microenvironment and a postdoctoral focus on the tumor immune system will position the candidate for a translational career investigating the role of aging on immunotherapy and mechanisms by which to improve immunotherapy responses in aged cancer patients.