CGRP remodels the acidic microenvironment and promotes pancreatic carcinoma progression by regulating NHE1 and CA9

Neurons can regulate cancer cells to modulate their survival and growth, the interplay between calcitonin gene-related peptide (CGRP) and the acidic tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) remains unknown.

Here, we reported that CGRP expression and neuronal activation markers p-ERK/p-CREB were significantly elevated in PDAC tissues. Exogenous CGRP promoted PANC02 cell proliferation and migration, whereas CGRP knockout suppressed orthotopic tumor growth. Mechanistically, CGRP upregulated the proton transporters NHE1 and CA9, facilitating H⁺ efflux and reducing extracellular pH, thereby exacerbating TME acidification. Clinical analysis revealed that high expression of NHE1 and CA9 correlated with poor prognosis in PDAC patients. Rimegepant, a CGRP receptor antagonist, inhibited orthotopic tumor growth and exhibited synergistic effects with gemcitabine.

In conclusion, our findings uncover a functional connection between CGRPergic sensory neurons and the acidic TME, identifying the CGRP signaling pathway as a potential therapeutic target for PDAC. Despite these findings, the mechanistic conclusions remain correlative and require further validation, and the generalizability to human PDAC warrants future investigation.