A brain-tumour axis links chronic stress to gastric cancer progression through NPY signalling

Chronic stress promotes gastric tumour growth, but the central neural pathways remain largely enigmatic. Here, we identify a brain-tumour axis, implicating the central amygdala (CeA) activity in promoting gastric cancer growth through sympathetic neuropeptide Y (NPY) signalling occurring within the tumour. Using clinical datasets, patient samples, pathway tracing, electrophysiology and chemogenetic manipulation, we demonstrate that stress selectively increases NPY Y1 receptor (NPY1R) synthesis in the patients gastric cancer tissue; moreover, the NPY1R density correlates with advanced cancer stage and poor prognosis. In mice, daily constraint chronic stress enhances CeA excitability and promotes sympathetic neurotransmitter norepinephrine release within the tumour microenvironment. Norepinephrine, in turn, increases tumour endogenous NPY/NPY1R production and the activation of downstream MAPK/Erk1/2 signalling pathway, which drives cancer cell proliferation and invasion. Manipulating CeA neuronal activity alone can regulate tumour growth, whereas selectively blocking tumour NPY1R prevents stress-induced tumour progression in vivo and cancer cell migration in vitro. This study identifies a central-to-peripheral circuit linking chronic stress to gastric cancer growth, and highlights NPY1R as a potential therapeutic target.