Extended Data Fig. 7: Graphical summary.
From: Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression
Unlike their corresponding normal tissues, NSCLC and COAD cancer cells with aberrant GAD1 expression hijack glutamine metabolism for GABA synthesis. Consequently, GABA accumulates within tumors. Rather than providing metabolic fuel or building blocks, GABA activates GABABR to enhance β-catenin signaling by repressing GSK-3β activity. On one hand, GABA-mediated β-catenin activation directly contributes to autonomous tumor growth; on the other hand, enhanced β-catenin signaling by cancer cells suppresses production of CCL4 and CCL5 production in tumor cells to create a non-T cell-inflamed microenvironment. Targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy.
