Melanoma is a highly aggressive type of skin cancer that accounts for the majority of all skin cancer-related deaths worldwide. Melanoma metastasis poses a poor prognosis with resistance to therapy and high mortality rate. Thus, it is imperative to explore molecular mechanisms governing melanoma metastasis to identify candidate diagnostic or prognostic markers and develop novel therapeutic opportunities. Galectin-3 (Gal-3) has emerged as a pleiotropic promoter of cancer initiation and progression, exerting varying activities depending on the cellular context and its interacting partner. Extracellular Gal-3 is involved in mediating crosstalk between melanoma cells and the tumor microenvironment (TME) through lattice formation, conferring survival advantages for tumor cells. However, whether intracellular Gal-3 promotes melanoma aggressive behavior remains unknown. Here, I explore extra- /intracellular expression of Gal-3 in melanoma patient sera, primary and metastatic melanoma samples, and several melanoma models and its causal role in metastatic behavior. In contrast to elevated Gal-3 in melanoma patient sera, Gal-3 expression was markedly downregulated in primary melanomas and further depressed in metastatic melanomas. Enforced silencing of Gal-3 in melanoma cells promoted migration, invasion, colony formation, xenograft growth, and activated the canonical oncogenic PI3K/AKT, MAPK/ERK, and Wnt/β-catenin signaling pathways. My data also provide evidence of a negative regulatory role for Gal-3 on the expression of nuclear factor of activated T cells (NFAT1) and its downstream metastasis-associated effector proteins, namely matrix metalloproteinase-3 (MMP-3), interleukin-8 (IL-8), and glypican-6 (GPC6) in melanoma cells. Importantly, these results highlight the tumor-suppressive function of Gal-3 in melanoma cells, emphasizing the negative crosstalk between Gal-3 and NFAT1 and its role in dictating melanoma metastasis, and introducing GPC6 as a candidate target of the Gal-3-NFAT1 axis in melanoma. Overall, studies conducted in this dissertation implicate tumor-intrinsic Gal-3 as a candidate prognostic indicator of metastatic risk in melanoma patients.
