The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration
Chiara Cencioni, Silvia Malatesta, Virginia Vigiano Benedetti, Valerio Licursi, Livia Perfetto, Federica Conte, Danilo Ranieri, Armando Bartolazzi, Martina Kunkl, Loretta Tuosto, Alberto Larghi, Geny Piro, Antonio De Agostini, Giampaolo Tortora, Vincenzo Corbo, Carmine Carbone, Francesco Spallotta
Abstract
BACKGROUND: Metabolic syndrome represents a pancreatic ductal adenocarcinoma (PDAC) risk factor. Metabolic alterations favor PDAC onset, which occurs early upon dysmetabolism. Pancreatic neoplastic lesions evolve within a dense desmoplastic stroma, consisting in abundant extracellular matrix settled by cancer associated fibroblasts (CAFs). Hereby, dysmetabolism and PDAC association was analyzed focusing on CAF functions. METHODS: PDAC development upon dysmetabolic conditions was investigated in: 1) high fat diet fed wild type immunocompetent syngeneic mice by orthotopic transplantation of pancreatic intraepithelial neoplasia (PanIN) organoids; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with/without an history of metabolic syndrome. RESULTS: The dysmetabolic-associated higher PDAC aggressiveness was paralleled by collagen fibril enrichment due to prolyl 4-hydroxylase subunit alpha 1 (P4HA1) increased function. Upon dysmetabolism, P4HA1 boosts collagen proline hydroxylation, intensifies collagen contraction strength, precluding PDAC infiltration. Noteworthy, semaglutide, an incretin agonist, prevents the higher dysmetabolism-dependent PDAC stromal deposition and allows T lymphocyte infiltration, reducing tumor development. CONCLUSIONS: These results shed light on novel therapeutic options for PDAC patients with metabolic syndrome aimed at PDAC stroma reshape.