Identifying Microenvironmental Factors Regulating Melanoma Promotion and Immune Evasion

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PROJECT SUMMARY This SERCA K01 application aims to provide the protected time and mentorship for Dr. Hyeongsun Moon, DVM, PhD to make the successful transition to a tenure-track, independent principal investigator. Dr. Moon is a veterinarian and cancer biologist that utilizes genetically engineered animal models with a long- term goal to establish a unique academic tumor microenvironment lab that encompasses all of his research skills. Under the guidance of his well-established mentors, cancer immunologist, Dr. William Murphy, PhD and comparative pathologist, Dr. Alexander Borowsky, MD and advisory committee members, the mentored research and career development period will solidify Dr. Moon’s expertise in cancer research using preclinical mouse models and the state-of-the-art immuno-oncology/pathology assessments, and prepare himself to become an independent academic researcher and establish his lab which aims to define the tumor microenvironment in cancer promotion, and ultimately find novel preventative and therapeutic strategies. The prestigious host institute, the University of California at Davis, the School of Veterinary Medicine and School of Medicine, and the Comprehensive Cancer Center, provides an excellent environment for both successful research accomplishment and academic career development. Cutaneous melanoma is the deadliest skin cancer with a continuous increase in its annual incidence rate. While genetic etiologies and risk factors are well-known, little is known about the mechanisms behind the factors governing melanoma promotion including immune evasive characteristics. This study seeks to identify regional niche factors regulating tumor outgrowth and response to immunotherapy. Based on preliminary data, this grant application focuses on the microenvironmental C-X-C motif chemokine 12 (CXCL12) signaling axis and its role in these processes. The central hypothesis of the proposed study is that microenvironmental CXCL12, also known as stromal cell- derived factor 1 (SDF-1), facilitates melanoma promotion and immune evasion via generating a pro- tumorigenic niche environment. The specific aims are: Specific Aim #1. Define the role of CXCL12 signaling axis in early melanoma promotion. Specific Aim #2. Define the role of tumor microenvironmental CXCL12 in melanoma immunotherapy. These studies will generate valuable information on how a specific chemokine signaling pathway promotes melanoma promotion and immune evasion in a genetically susceptible population and will lay the foundation for a future R01 application aimed at deciphering what factors play a critical role in melanoma outgrowth and oncogenic communication networks with immune cells. Overall, this award will grant competitiveness and independence to Dr. Moon particularly on targeting the tumor microenvironment for successful melanoma treatment and will lay the foundation towards a successful tenure-track researcher.