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cd-23-0389_supplementary_video_1_suppsv1.mp4 (9.3 MB)

Supplementary Video 1 from GABA Regulates Electrical Activity and Tumor Initiation in Melanoma

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posted on 2023-10-05, 07:20 authored by Mohita Tagore, Emiliano Hergenreder, Sarah C. Perlee, Nelly M. Cruz, Laura Menocal, Shruthy Suresh, Eric Chan, Maayan Baron, Stephanie Melendez, Asim Dave, Walid K. Chatila, Jeremie Nsengimana, Richard P. Koche, Travis J. Hollmann, Trey Ideker, Lorenz Studer, Andrea Schietinger, Richard M. White

3D rendering of melanoma/keratinocyte contacts in zebrafish embryos

Funding

Melanoma Research Alliance (MRA)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Pershing Square Sohn Cancer Research Alliance (PSSCRA)

Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)

Harry J. Lloyd Charitable Trust (HJLCT)

American Cancer Society (ACS)

NIH Office of the Director (OD)

National Institutes of Health (NIH)

Melanoma Research Foundation (MRF)

History

ARTICLE ABSTRACT

Oncogenes can initiate tumors only in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors in keratinocytes. Electron microscopy demonstrates specialized cell–cell junctions between keratinocytes and melanoma cells, and multielectrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte cocultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that GABAergic signaling across the skin microenvironment regulates the ability of oncogenes to initiate melanoma. This study shows evidence of GABA-mediated regulation of electrical activity between melanoma cells and keratinocytes, providing a new mechanism by which the microenvironment promotes tumor initiation. This provides insights into the role of the skin microenvironment in early melanomas while identifying GABA as a potential therapeutic target in melanoma.See related commentary by Ceol, p. 2128.This article is featured in Selected Articles from This Issue, p. 2109

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