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GABA Regulates Electrical Activity and Tumor Initiation in Melanoma.
Tagore, Mohita; Hergenreder, Emiliano; Perlee, Sarah C; Cruz, Nelly M; Menocal, Laura; Suresh, Shruthy; Chan, Eric; Baron, Maayan; Melendez, Stephanie; Dave, Asim; Chatila, Walid K; Nsengimana, Jeremie; Koche, Richard P; Hollmann, Travis J; Ideker, Trey; Studer, Lorenz; Schietinger, Andrea; White, Richard M.
Afiliación
  • Tagore M; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hergenreder E; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Perlee SC; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
  • Cruz NM; Weill Graduate School of Medical Sciences of Cornell University, New York, New York.
  • Menocal L; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Suresh S; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Chan E; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Baron M; Weill Graduate School of Medical Sciences of Cornell University, New York, New York.
  • Melendez S; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Dave A; Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Chatila WK; Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, California.
  • Nsengimana J; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Koche RP; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hollmann TJ; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Ideker T; Biostatistics Research Group, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • Studer L; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Schietinger A; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • White RM; Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, California.
Cancer Discov ; 13(10): 2270-2291, 2023 Oct 05.
Article en En | MEDLINE | ID: mdl-37553760
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. SIGNIFICANCE: 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Melanoma Límite: Animals / Humans Idioma: En Revista: Cancer Discov Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Melanoma Límite: Animals / Humans Idioma: En Revista: Cancer Discov Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos