研究动态
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γ-氨基丁酸调控黑色素瘤的电活动和肿瘤发生。

GABA regulates electrical activity and tumor initiation in melanoma.

发表日期:2023 Aug 09
作者: 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
来源: Cancer Discovery

摘要:

癌基因只能在特定的细胞背景下引发肿瘤,这被称为致癌能力。在黑色素瘤中,微环境中的细胞是否能赋予这种能力尚不清楚。使用斑马鱼转基因结合人类组织的方法,我们证明角质细胞和黑色素细胞之间的伽玛氨基丁酸信号促进了BRAFV600E引起的黑色素瘤的发生。黑色素瘤细胞中合成伽玛氨基丁酸,然后作用于角质细胞上的伽玛氨酸A受体。电子显微镜观察显示角质细胞和黑色素瘤细胞之间存在特殊的细胞间连接,多电极阵列分析显示伽玛氨基丁酸通过抑制黑色素瘤/角质细胞共培养体中的电活动来发挥作用。通过遗传和药物干扰伽玛氨基丁酸的合成,可以消除体内黑色素瘤的发生。这些数据表明,皮肤微环境中的伽玛氨基丁酸信号调节致癌基因引发黑色素瘤的能力。
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.