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

Sabu Kattuman, Emma Elizabet E; Teegala, Lakshminarayan Redd R; Katari, Venkatesh; Darzi, Somayeh; Saladi, Srinivas Vino V; de la Serna, Ivana; Thodeti, Charles K; Paruchuri, Sailaja

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

Autocrine CysLTR-ERK/YAP signaling drives melanoma progression and reveals a targetable oncogenic GPCR axis Article (Faculty180)