Characterize the role of cholinergic signalling in pancreatic cancer liver metastasis

Cholinergic signalling, traditionally attributed to the parasympathetic nervous system, is increasingly recognized as an immunoregulatory pathway in diverse disease contexts. Acetylcholine, the primary neurotransmitter in cholinergic signalling, is reported to be secreted by immune cells and plays an important role in hepatocellular carcinoma, liver regeneration, and metabolic dysfunction-associated steatohepatitis. However, whether immune cell-derived ACh influences cancer metastasis to the liver remains unknown. Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, providing a relevant model to interrogate the neuroimmune mechanisms that shape the metastatic microenvironment. Using a spontaneous liver metastasis model generated by orthotopic or splenic injection of murine pancreatic cancer cells, we observed a marked induction of the ACh-synthesizing enzyme choline acetyltransferase (ChAT) in immune cells during liver metastatic progression, suggesting that immune cells contribute to a local immune-derived cholinergic niche. These findings identify a previously unrecognized cholinergic-immune axis in the pancreatic cancer metastatic niche, where immune-derived ACh increases during liver metastasis. Targeting neuroimmune pathways may offer new strategies to modulate the liver metastatic microenvironment in PDAC.