The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration
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...
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03263-w |
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| author | 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 Agostini Giampaolo Tortora Vincenzo Corbo Carmine Carbone Francesco Spallotta |
| author_facet | 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 Agostini Giampaolo Tortora Vincenzo Corbo Carmine Carbone Francesco Spallotta |
| author_sort | Chiara Cencioni |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d098e291964841d2a7d39364dab547be |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-d098e291964841d2a7d39364dab547be2025-01-26T12:57:52ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144112010.1186/s13046-024-03263-wThe GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltrationChiara Cencioni0Silvia Malatesta1Virginia Vigiano Benedetti2Valerio Licursi3Livia Perfetto4Federica Conte5Danilo Ranieri6Armando Bartolazzi7Martina Kunkl8Loretta Tuosto9Alberto Larghi10Geny Piro11Antonio Agostini12Giampaolo Tortora13Vincenzo Corbo14Carmine Carbone15Francesco Spallotta16Institute of System Analysis and Informatics “Antonio Ruberti”, National Research Council (IASI-CNR)Department of Biology and Biotechnologies “Charles Darwin”, Sapienza UniversityDepartment of Translational Medicine, Catholic University of the Sacred HeartInstitute of Molecular Biology and Pathology, National Research Council (IBPM-CNR)Department of Biology and Biotechnologies “Charles Darwin”, Sapienza UniversityInstitute of System Analysis and Informatics “Antonio Ruberti”, National Research Council (IASI-CNR)Dipartimento Di Scienze Della Vita, Della Salute E Delle Professioni Sanitarie. Università Degli Studi “Link Campus University”Pathology Research Laboratory, Sant’ Andrea University HospitalDepartment of Biology and Biotechnologies “Charles Darwin”, Sapienza UniversityDepartment of Biology and Biotechnologies “Charles Darwin”, Sapienza UniversityDigestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCSMedical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCSMedical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCSDepartment of Translational Medicine, Catholic University of the Sacred HeartDepartment of Engineering for Innovation Medicine (DIMI), University and Hospital Trust of VeronaMedical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCSDepartment of Biology and Biotechnologies “Charles Darwin”, Sapienza UniversityAbstract 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.https://doi.org/10.1186/s13046-024-03263-wPancreatic ductal adenocarcinomaCancer associated fibroblastsDiabetesObesityCollagen deposition |
| spellingShingle | 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 Agostini Giampaolo Tortora Vincenzo Corbo Carmine Carbone Francesco Spallotta The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration Journal of Experimental & Clinical Cancer Research Pancreatic ductal adenocarcinoma Cancer associated fibroblasts Diabetes Obesity Collagen deposition |
| title | The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration |
| title_full | The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration |
| title_fullStr | The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration |
| title_full_unstemmed | The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration |
| title_short | The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration |
| title_sort | glp 1r agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring t lymphocyte infiltration |
| topic | Pancreatic ductal adenocarcinoma Cancer associated fibroblasts Diabetes Obesity Collagen deposition |
| url | https://doi.org/10.1186/s13046-024-03263-w |
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