Open AccessCancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression
Author(s) -
De Huang,
Yan Wang,
J. Will Thompson,
Tao Yin,
Peter Alexander,
Diyuan Qin,
Poorva Mudgal,
Haiyang Wu,
Yaosi Liang,
Licheng Tan,
Christopher C. Pan,
Lifeng Yuan,
Ying Wan,
Qi-Jing Li,
XiaoFan Wang
Publication year - 2022
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-021-00820-9
Subject(s) - glutamate receptor , biology , cancer research , microbiology and biotechnology , glutamine , gabab receptor , neurotransmitter , cancer cell , immunosuppression , glutamate decarboxylase , cancer , receptor , biochemistry , immunology , gabaa receptor , amino acid , genetics , enzyme
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 GABA B 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 GABA B R 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.