A self-amplifying nerve-fibroblast circuit drives colorectal cancer progression.

Nerves and cancer-associated fibroblasts (CAFs) have each been shown to regulate cancer progression directly. However, whether these cells interact to control tumor progression remains largely unknown. We show that in colorectal cancer (CRC), cholinergic stimulation induces CHRM3/Gq-dependent NTN1 secretion from CAFs, which in turn enhances intratumor cholinergic innervation. Within this feedforward loop, cholinergic stimulation promotes CRC growth directly through tumoral CHRM3/Gq-mediated YAP activation, while CAF-derived NTN1 promotes CRC growth and epithelial-to-mesenchymal transition-like programs via UNC5B-PI3K/AKT signaling. Chemogenetic activation of cholinergic neurons or fibroblast activation of the M3 receptor/Gq promotes tumoral YAP and AKT signaling and CRC progression. Conversely, blocking CHRM3 or NTN1 suppresses these pathways and improves mouse survival. In human CRC, high NTN1 expression is associated with a mesenchymal-like subtype and poor patient outcomes. These findings suggest that the neuro-mesenchymal interaction is central to CRC progression and could be therapeutically targeted with a CHRM3 antagonist or NTN1-blocking antibody.