αvβ3-induced epithelial cancer progression via macrophage recruitment

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Project Summary/Abstract It has recently become clear that carcinogenesis and cancer progression involves dysregulation of immune cells within the tumor microenvironment. The particular interest of this proposal are how tumor cells develop tactics to manipulate immune cells to facilitate cancer progression, and how chronic inflammation induced immunosuppression accelerates carcinogenesis. Dr. Wettersten recently published that tumor cell expression of a cell adhesion receptor, integrin αvβ3, is associated with the enrichment of tumor-associated macrophages (TAMs), which are known to promote immune suppression and prevent the influx of cytotoxic T cells. Her new preliminary studies reveal that αvβ3 expression on lung cancer cells is sufficient to recruit TAMs and that inflammatory mediators can induce αvβ3 expression both on normal lung epithelium as well as lung cancer cells. Together, these findings suggest inflammation can induce tumor cell expression of αvβ3, which in turn leads to TAM accumulation, immune suppression, and tumor progression. Furthermore, inflammation induced αvβ3 expression on lung epithelium may contribute to the well-known relationship between inflammation and cancer. The overall goals of this study are to understand how αvβ3+ cancer cells promote a pro- tumor/immunosuppressive microenvironment during cancer progression and how αvβ3 expression on normal lung epithelium induces inflammation-mediated carcinogenesis. Aim 1 will determine if TAM enrichment factors from αvβ3+ cancer cells promote an immunosuppressive microenvironment. The goal of Aim 2 is to target integrin αvβ3+ cancer cells to shift the tumor immune profile from pro-tumor to anti-tumor. Aim 3 will assess if inflammation-induced expression of integrin αvβ3 on lung epithelial cells accelerates carcinogenesis. To achieve these aims, the expression of αvβ3 will be genetically modified in immunocompetent mouse models of lung cancer and inflammation to reveal how αvβ3+ cells exploit the immune system to enable cancer development and progression. Understanding this process will lead to the development of novel therapeutic strategies to strengthen the anti-tumor immune response. Dr. Wettersten’s career goal is to become an independent investigator in an academic setting. She will leverage her dual training as a veterinarian and cancer biologist to generate new therapeutic approaches targeting the communication between the tumor microenvironment and cancer cells. While her project is strongly supported by her recent findings with Dr. Cheresh, exploring the impact of αvβ3+ cancer cells in the tumor microenvironment is distinct from Dr. Cheresh’s existing work, and the novel mouse models established in this study will provide a foundation for her to further investigate the cancer cell-microenvironment interaction. Dr. Cheresh and her other collaborators at UCSD will give her access to world-class facilities, equipment, and animal models, providing her with an ideal environment to accomplish the proposed work and launch her career as an independent investigator.