Autocrine CysLT1R-ERK/YAP signaling drives melanoma progression and reveals a targetable oncogenic GPCR axis.

Cutaneous melanoma remains the most lethal skin cancer due to profound tumor heterogeneity and the frequent development of resistance to current therapies. Here, we identify the cysteinyl leukotriene receptor 1 (CysLT1R) as a previously unrecognized driver of melanoma progression. Analysis of bulk RNA-sequencing datasets from The Cancer Genome Atlas (TCGA) revealed significantly elevated CysLT1R transcript in metastatic tumors compared to primary tumors. Functional studies in murine and human melanoma cells demonstrated that leukotriene D4 (LTD4)-mediated activation of CysLT1R promotes melanoma cell proliferation and invasion through the parallel engagement of YAP and ERK signaling pathways. Notably, melanoma cells express LTC4 synthase and secrete cysteinyl leukotrienes, establishing a constitutive autocrine signaling loop that sustains CysLT1R activity independently of the host niche. Genetic ablation or pharmacological inhibition of CysLT1R with MK571 significantly attenuated tumor growth in vivo and was associated with inhibition of the YAP-LOXL-2 signaling axis. In addition, studies using Cysltr1-/- mice reveal that host-derived CysLT1R signaling within the tumor microenvironment also contributes to melanoma progression. Together, these findings uncover a previously unrecognized pro-tumorigenic CysLT1R-ERK/YAP,LOXL-2 signaling circuit that promotes cutaneous melanoma progression and highlight CysLT1R as a potential therapeutic target for melanoma.