Sensory neuropeptide CGRP and its co-receptor RAMP1 drive tumour cell growth in gastrointestinal cancers

Objective: The gastrointestinal (GI) tract is densely innervated, forming a critical network that secretes neuropeptides essential for gut function. Tumour cells are highly adaptive and exploit their microenvironment, including nerves, to support and accelerate growth. However, the mechanisms by which tumour cells interact with neuropeptides in human GI cancers remain poorly understood. We aimed to investigate the expression and function of the sensory neuropeptide calcitonin gene-related peptide (CGRP) and its receptor component, receptor activity-modifying protein 1 (RAMP1), and to elucidate novel mechanisms by which cancer cells exploit neuropeptides. Methods and analysis: We analysed 180 patient samples using multiplex immunohistochemistry to assess CGRP and RAMP1 expression in primary colorectal cancer (CRC), CRC liver metastases and gastric cancers (GC). RAMP1 expression was correlated with patient demographics (age and gender) and tumour characteristics, including pathological features and molecular and genomic subtypes. RAMP1 expression and association with patient survival were evaluated using data from the Cancer Genome Atlas. The function of CGRP on tumour cell lines and patient-derived tumour organoids was assessed via in vitro stimulation assays and RNA sequencing. Results: RAMP1 expression in tumours was significantly associated with reduced survival in both CRC and GC. Over 50% of CRC and 60% of GC cells from patient samples expressed RAMP1. RAMP1 expression was enriched in tumours with microsatellite instability (MSI) and in patients with GC younger than 50 years. CGRP was abundantly expressed in stromal regions indicative of nerve fibres near tumour cells, and unexpectedly, CGRP was also produced by CRC and GC cells. Finally, CGRP stimulation enhanced tumour cell growth in a RAMP1-dependent manner, inducing genes linked to proliferation, metabolism and migration. Conclusion: This study reveals novel mechanisms by which the neuropeptide CGRP promotes tumour growth in GI cancers. We expand upon existing knowledge by demonstrating that tumour cells are a source of CGRP, highlighting potential therapeutic targets within the tumour-nerve axis.