Work

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

Year: 2026

Type: article

Abstract: 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 (CysLT 1 R) as a previously unrecognized driver of melanoma progression. Analysis of bulk RNA-sequencing datasets from The Cancer Genome Atlas (TCGA) revealed significantly elevated CysLT 1 R transcript in metastatic tumors compared to primary tumors. Functional studies in murine and human melanoma cells demonstrated that leukotriene D 4 (LTD 4 )-mediated activation of CysLT 1 R promotes melanoma cell proliferation and invasion through the parallel engagement of YAP and ERK signaling pathways. Notably, melanoma cells express LTC 4 synthase and secrete cysteinyl leukotrienes, establishing a constitutive autocrine signaling loop that sustains CysLT 1 R activity independently of the host niche. Genetic ablation or pharmacological inhibition of CysLT 1 R 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 CysLT 1 R signaling within the tumor microenvironment also contributes to melanoma progression. Together, these findings uncover a previously unrecognized pro-tumorigenic CysLT 1 R-ERK/YAP,LOXL-2 signaling circuit that promotes cutaneous melanoma progression and highlight CysLT 1 R as a potential therapeutic target for melanoma.

Source: Oncogene

DOI: 10.1038/s41388-026-03919-1