Exploring palmitoylation dynamics: impacts on Cadherin-Catenin adhesion and lipid metabolism in the progression of melanoma lung metastasis

Melanoma, a major cause of cancer deaths, often metastasizes to the lungs and other organs, leading to a low five-year survival rate of 15-20% in advanced stages. The effective treatment of metastatic melanoma, including in the lungs, remains a significant challenge. Therefore, research focusing on understanding and combating pulmonary metastasis of melanoma is vital for improving diagnostics, treatment strategies, and overall patient outcomes, while also providing broader insights into cancer metastasis mechanisms. Protein palmitoylation, a reversible form of lipid modification, is essential for mediating dynamic cell-cell interactions by enhancing protein hydrophobicity, membrane association, and functional specificity. This post-translational modification enables the assembly of protein complexes and signaling platforms vital for cell adhesion and intercellular communication. Despite its importance, the role of palmitoylation in human disease is significantly understudied. Here, we present preliminary data to show the involvement of ZDHHC13, a palmitoyl-transferase, in metastatic dissemination and the immune-modulatory microenvironment, as an underexplored class of potential therapeutic targets. We find that ZDHHC13, suppresses metastatic dissemination by palmitoylation of CTNND1, leading to stabilization of E- cadherin. Significantly, ZDHHC13 also reshapes the tumor immune microenvironment by suppressing lysophosphatidylcholine (LPC) synthesis in melanoma cells, leading to inhibition of M2-like tumor-associated macrophages (TAMs) that we show degrades E-cadherin via MMP12 expression. Consequently, ZDHHC13 activity suppresses tumor growth and metastasis in immunocompetent mice. Furthermore, ZDHHC13 signaling is disrupted in NF1-mutated melanomas, suggesting a potential synergistic interaction between NF1 mutation and ZDHHC13 signaling loss. Based on these findings, we hypothesize that ZDHHC13 inhibits melanoma metastasis through a dual mechanism involving both cancer cell-intrinsic and immune-modulatory pathways within the tumor microenvironment. We also propose that activation of ZDHHC13 signaling may represent a novel therapeutic strategy for metastatic melanomas harboring NF1 mutations. Our research aims are designed to validate these hypotheses by: (1) defining ZDHHC13's role in cadherin regulation and metastasis suppression; (2) exploring ZDHHC13’s influence on immune responses in metastatic melanoma; and (3) assessing ZDHHC13 pathway activation as a therapeutic approach, especially for NF1-mutated tumors. Completion of this study will illuminate new strategies for combating melanoma progression and metastasis, with broader implications for cancer metastasis treatment. Project Number: 1R37CA295784-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Shuyang Chen | Institution: CLEVELAND CLINIC LERNER COM-CWRU, CLEVELAND, OH | Award Amount: $487,468 | Activity Code: R37 | Study Section: Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM] View on NIH RePORTER: https://reporter.nih.gov/project-details/11225205