Investigating the role of melanoma-adipocyte cell junctions in heterotypic communication and tumor progression

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PROJECT SUMMARY Melanoma is the most lethal skin cancer. Few treatment options exist for patients with metastatic disease. Upon tumorigenesis, melanoma cells invade into dermal and subcutaneous tissues and then eventually metastasize to distant organs, encountering and interacting with various microenvironmental cell types. The tumor microenvironment plays a significant role in melanoma progression. Lipid-laden cells called adipocytes are located in the subcutaneous layer of the skin. Recent work from our lab demonstrated that adipocytes serve as a source of fatty acids that fuel melanoma growth and invasion. Although melanoma tumors are often in direct contact with adipocytes, the mechanism of melanoma-adipocyte communication is unclear. Our preliminary data identify the presence of gap junctions between melanoma cells and adipocytes. These data point to Adipocyte Cell Adhesion Molecule (ACAM) as a potential mediator of melanoma-adipocyte adhesion. In Aim 1, we will investigate the mechanism of melanoma-adipocyte adhesion and its role in tumor progression. ACAM mediates cell-cell adhesion through homophilic binding. Our own data show that ACAM is upregulated in melanoma cells that are co-cultured with adipocytes. Loss of ACAM in melanoma cells abrogates gap junctional communication with adipocytes. We hypothesize that ACAM is a key regulator of melanoma-adipocyte contact and communication. Using human melanoma cell lines and adipocytes in a co-culture system, we will identify changes in melanoma-adipocyte adhesion and cell-cell communication upon knock out of ACAM. We will engineer adipocyte-restricted ACAM knockout zebrafish to delineate the effects of adipocyte-specific ACAM loss on tumor progression. In Aim 2, we will elucidate the mechanism and functional consequences of melanoma-adipocyte gap junctions. Gap junctions mediate the transfer of ions, small metabolites, and secondary messengers such as cAMP, a key activator of lipolysis, between neighboring cells. We hypothesize that melanoma-adipocyte gap junctions facilitate the direct transfer of signaling molecules between coupled cells, ultimately activating tumor-promoting pathways such as lipolysis. To gain insight into the molecular basis for melanoma-adipocyte gap junctions, we will first identify the connexin(s) composition of these channels. We will also study the role of melanoma-adipocyte gap junctions in lipolysis and tumor progression using an in vivo zebrafish subcutaneous transplant model. By investigating how melanoma cells interact with adjacent adipocytes, we seek to delineate the impact of adipocytes on tumor progression and identify novel therapeutic targets of the tumor microenvironment.