PUBLICATION
GABA regulates electrical activity and tumor initiation in melanoma
- Authors
- Tagore, M., Hergenreder, E., Perlee, S.C., Cruz, N.M., Menocal, L., Suresh, S., Chan, E., Baron, M., Melendez, S., Dave, A., Chatila, W.K., Nsengimana, J., Koche, R.P., Hollmann, T.J., Ideker, T., Studer, L., Schietinger, A., White, R.M.
- ID
- ZDB-PUB-230810-58
- Date
- 2023
- Source
- Cancer discovery 13(10): 2270-2291 (Journal)
- Registered Authors
- White, Richard M.
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Transformation, Neoplastic/genetics
- Humans
- Keratinocytes
- Melanocytes/pathology
- Melanoma*/drug therapy
- Melanoma*/genetics
- Melanoma*/pathology
- Skin
- Tumor Microenvironment
- Zebrafish
- gamma-Aminobutyric Acid
- PubMed
- 37553760 Full text @ Cancer Discov
Citation
Tagore, M., Hergenreder, E., Perlee, S.C., Cruz, N.M., Menocal, L., Suresh, S., Chan, E., Baron, M., Melendez, S., Dave, A., Chatila, W.K., Nsengimana, J., Koche, R.P., Hollmann, T.J., Ideker, T., Studer, L., Schietinger, A., White, R.M. (2023) GABA regulates electrical activity and tumor initiation in melanoma. Cancer discovery. 13(10):2270-2291.
Abstract
Oncogenes can only initiate tumors 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 on keratinocytes. Electron microscopy demonstrates specialized cell-cell junctions between keratinocytes and melanoma cells, and multi-electrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte co-cultures. 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping