Abstract 5692: Distinct effectors of FSTL1 promote melanoma growth and angiogenesis and FSTL1 blockade mitigates resistance to BRAF and MEK inhibitors

Melanoma is a highly lethal form of skin cancer due to its propensity for metastasis through angiogenesis, which confers melanoma initiating cells with resistance to BRAF and MEK inhibitors. However, current drugs for targeting angiogenesis have shown limited efficacy, highlighting the need to develop new anti-angiogenic therapies to effectively combat this devasting malignancy. Here, we found that Follistatin-like 1 (FSTL1) expression is significantly increased in metastatic melanoma, and correlates with higher microvessel density, and poor prognosis. FSTL1 is both required and sufficient for the growth, metastasis, and angiogenesis of melanoma. FSTL1 functions downstream of SOX10-DLC1-FOXK1 to mediate its oncogenic activity, which can be inhibited by FSTL1 neutralizing antibody (FSTL1 nAb). Mechanistically, intracellular FSTL1 promotes G1/S transition in proliferative melanoma cells by activating an AKT/Lamin B2 axis. Secreted FSTL1 activates endothelial expression of TMSB4X to induce nuclear NF-kB-dependent regulation of angiogenesis. Furthermore, FSTL1 expression is selectively upregulated in melanoma-initiating cells that are resistant to BRAF and MEK inhibitors, driving stemness through interactions with the tumor microvasculature. Treatment with FSTL1 nAb depletes melanoma-initiating cells and slows down drug resistance development, suggesting that FSTL1 nAb may be a promising adjunct therapy to BRAF and MEK inhibitors for melanoma treatment. Citation Format: Umar Patel, Jiaying Ng, Chiu Wang Chau, Alex To, Ryohichi Sugimura, Martin Cheung. Distinct effectors of FSTL1 promote melanoma growth and angiogenesis and FSTL1 blockade mitigates resistance to BRAF and MEK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5692.