An Itch Receptor Drives Melanoma
- 1Johns Hopkins University School of Medicine
Abstract
Mas-Related GPCR X4 (MRGPRX4) is a sensory neuron-restricted receptor for cholestatic itch. Here, we identify MRGPRX4 as an unexpected melanoma driver. MRGPRX4 is upregulated in melanoma and is confined to invasive, neural-crest-like and pre-EMT states associated with dedifferentiation and therapy resistance. Ectopic MRGPRX4 expression in mouse melanocytes drives 100% penetrant, highly metastatic melanoma, demonstrating oncogenic behavior. MRGPRX4 promotes melanoma cell proliferation and invasion through basal, ligand-independent, PI3K-AKT-MAPK activation. Multi-omics links MRGPRX4 expression to a mesenchymal/neural-crest-like program that defines a distinct invasive MRGPRX4? niche. Comparing transcptomics of MRGPRX4-driven tumors shows a broad overlap with BRAF/NRAS-driven tumors; however, the MRGPRX4 model also enriches an ECM-rich, invasive neural crest-like melanoma state. MRGPRX4 further remodels the tumor microenvironment toward an immunosuppressive, checkpoint-high state enriched in suppressive myeloid cells. Pharmacologic MRGPRX4 inhibition suppresses basal signaling and limits melanoma growth and invasion. In sum, melanoma exploits MRGPRX4 to acquire an invasive and immunosuppressive phenotype, nominating this somatosensory GPCR as a promising therapeutic target.
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BibTeX
@misc{gour2026itch,
title = {{An Itch Receptor Drives Melanoma}},
author = {N. Gour and A. Atakkatan and M. Akbarzadeh and H. M. Yong and A. Magesh and Z. Wu and H. Joo and Y. Chhabra and J. Peng and A. Weeraratna and M. Laplante and S. Lajoie and X. Dong},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.01.729383},
url = {https://www.biorxiv.org/content/10.64898/2026.06.01.729383v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - An Itch Receptor Drives Melanoma
AU - N. Gour
AU - A. Atakkatan
AU - M. Akbarzadeh
AU - H. M. Yong
AU - A. Magesh
AU - Z. Wu
AU - H. Joo
AU - Y. Chhabra
AU - J. Peng
AU - A. Weeraratna
AU - M. Laplante
AU - S. Lajoie
AU - X. Dong
PY - 2026
DA - 2026/06/01
PB - bioRxiv
DO - 10.64898/2026.06.01.729383
UR - https://www.biorxiv.org/content/10.64898/2026.06.01.729383v2
AB - Mas-Related GPCR X4 (MRGPRX4) is a sensory neuron-restricted receptor for cholestatic itch. Here, we identify MRGPRX4 as an unexpected melanoma driver. MRGPRX4 is upregulated in melanoma and is confined to invasive, neural-crest-like and pre-EMT states associated with dedifferentiation and therapy resistance. Ectopic MRGPRX4 expression in mouse melanocytes drives 100% penetrant, highly metastatic melanoma, demonstrating oncogenic behavior. MRGPRX4 promotes melanoma cell proliferation and invasion through basal, ligand-independent, PI3K-AKT-MAPK activation. Multi-omics links MRGPRX4 expression to a mesenchymal/neural-crest-like program that defines a distinct invasive MRGPRX4? niche. Comparing transcptomics of MRGPRX4-driven tumors shows a broad overlap with BRAF/NRAS-driven tumors; however, the MRGPRX4 model also enriches an ECM-rich, invasive neural crest-like melanoma state. MRGPRX4 further remodels the tumor microenvironment toward an immunosuppressive, checkpoint-high state enriched in suppressive myeloid cells. Pharmacologic MRGPRX4 inhibition suppresses basal signaling and limits melanoma growth and invasion. In sum, melanoma exploits MRGPRX4 to acquire an invasive and immunosuppressive phenotype, nominating this somatosensory GPCR as a promising therapeutic target.
ER -