Abstract LB084: Fzd7 promotes melanoma growth via fostering an immunosuppressive tumor microenvironment

Abstract Melanoma is one of the deadliest skin neoplasms and its incidence has been increasing at a continuous pace. Standard monotherapies, FDA-approved targeted, combination, and immunological therapies have shown limited efficacy against melanomas. Frizzled 7 (Fzd7), a member of typical G protein coupled receptor (GPCR), plays an important role in stem cell biology, cancer development and progression. The mammalian frizzled gene family mediates canonical and non-canonical Wnt signaling pathways, which are highly activated in melanoma. We found that Fzd7 is highly expressed in multiple melanoma cell lines. To determine the role of Fzd7 in melanoma, we used siRNA to knockdown (KD) Fzd7 in YUMM1.7 cells and found Fzd7 promotes melanoma invasion. We observed similar phenotype in Yumm1.7 Fzd7 knockout (KO) cells generated by CRISPR/Cas9. Interestingly, Fzd7 KO cells showed significant reduction in primary tumor growth when grafted in C57BL/6 mice. To understand the mechanism of Fzd7 in melanoma, bulk RNA-Seq was performed. The top 6 differentially downregulated genes were Ace, Cacng7, Gas6, Htatip2, Pcdhb15, and Pcdhb20. We validated the changes by RT-qPCR in all three clones. KD of all these genes reduced invasion in Yumm1.7 cells. Gas6 activates melanoma drivers MAPK, PI3K and JAK/STAT via immune evasion. We found that Fzd7 KO tumors showed reduced Gas6 expression, and more TIL (CD4+, CD8+ cells) compared to WT YUMM1.7 cells, suggesting an immunosuppressive role of Fzd7 in melanoma. Overall, our results demonstrate that Fzd7 is involved in multiple aspects of melanomagenesis such as angiogenesis, cell adhesion, ion channeling and KO of Fzd7 fosters a robust antitumor response to inhibit melanoma growth. Citation Format: Minakshi Nihal, Sheikh A. Umar, Nihal Ahmad, Hao Chang. Fzd7 promotes melanoma growth via fostering an immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB084.