Whiles significant progress has been made in the development of new therapeutics to control malignant melanoma, the overall 5-year survival of patients with metastatic disease remains low in the majority of treated subjects. Thus, there is an urgent need for a more detailed understanding of how immune and inflammatory mechanisms govern melanoma progression in order to enhance long-term durable responses in a larger percentage of patients. Evidence indicates that immune infiltrates within the tumor microenvironment such as macrophages play critical roles in angiogenesis, tumor growth and escape from immune control. Melanomas often use an adaptive strategy of actively reprogramming stromal elements towards an immunosuppressive phenotype. Tumor associated macrophages (TAM) can modify both endothelial and T-cell behavior, thereby regulating angiogenesis, tumor growth and the efficacy of many cancer therapies. Identifying novel pro- angiogenic and immune suppressive factors generated by TAMs may provide new therapeutic opportunities and contribute to a more in depth understanding of how the tumor microenvironment controls melanoma growth. To this end, we made the surprising observation that an evolutionarily conserved RGDKGE containing collagen epitope can be generated by M2-like macrophages, and its expression was elevated over 3-fold within the circulation of a cohort of melanoma patients. Remarkably, this RGDKGE collagen epitope, but not other RGD collagen peptides, enhanced endothelial cell growth, stress fiber formation, nuclear translocation of the Yes-associated protein YAP, and induced a dose-dependent angiogenic and pro-inflammatory response in vivo. Based on these and other data, we will test the hypothesis that the RGDKGE epitope regulates angiogenesis and tumor growth by a novel integrin-YAP-dependent mechano-transduction pathway leading to the initiation of a pro-angiogenic signaling program.
Identifying a previously unrecognized mechanism by which tumor-associated macrophages generate a pro- angiogenic and immunosuppressive collagen fragment that regulates melanoma growth may lead to the development of more effective treatment strategies. The proposal will test the hypothesis that a highly conserved RGDKGE containing collagen epitope regulates angiogenesis and tumor growth by a novel integrin- YAP-dependent mechano-transduction pathway leading to the initiation of a pro-angiogenic and inflammatory signaling program. Our studies will contribute to a more in-depth molecular understanding of the mechanisms by which cooperative interactions between distinct stromal cell compartments regulates angiogenesis and tumor growth and may contribute to the development of a new treatment paradigm for more effective and durable management for malignant melanoma.