Author:
Agostini Antonio,Guerriero Ilaria,Piro Geny,Quero Giuseppe,Roberto Luca,Esposito Annachiara,Caggiano Alessia,Priori Lorenzo,Scaglione Giulia,De Sanctis Francesco,Sistigu Antonella,Musella Martina,Larghi Alberto,Rizzatti Gianenrico,Lucchetti Donatella,Alfieri Sergio,Sgambato Alessandro,Bria Emilio,Bizzozero Laura,Arena Sabrina,Ugel Stefano,Corbo Vincenzo,Tortora Giampaolo,Carbone Carmine
Abstract
Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance.
Methods
We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy.
Results
Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration.
Conclusions
Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC.
Funder
Associazione Italiana per la Ricerca sul Cancro
Agenzia Italiana del Farmaco, Ministero della Salute
Ministero dell'Università e della Ricerca
Ministero dell’Istruzione, dell’Università e della Ricerca
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine