Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.

De Huang, Yan Wang, J Will Thompson, Tao Yin, Peter B Alexander, Diyuan Qin, Poorva Mudgal, Haiyang Wu, Yaosi Liang, Lianmei Tan, Christopher Pan, Lifeng Yuan, Ying Wan, Qi-Jing Li, Xiao-Fan Wang

Nature cell biology 2022 Feb

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Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression. © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

De Huang, Yan Wang, J Will Thompson, Tao Yin, Peter B Alexander, Diyuan Qin, Poorva Mudgal, Haiyang Wu, Yaosi Liang, Lianmei Tan, Christopher Pan, Lifeng Yuan, Ying Wan, Qi-Jing Li, Xiao-Fan Wang. Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression. Nature cell biology. 2022 Feb;24(2):230-241