Unraveling the role of O-glycosylation in pancreatic ductal adenocarcinoma.

Description du projet

Glycosylation dans le cancer du pancréas

La glycosylation est une modification post-transcriptionnelle courante des protéines et des lipides. Elle joue un rôle central dans la régulation des fonctions cellulaires et des réponses immunitaires. L’adénocarcinome canalaire pancréatique (AFCD) se caractérise par des schémas de glycosylation distincts. Avec le soutien du programme Actions Marie Skłodowska-Curie, le projet GlycoPDAC étudiera comment la glycosylation détermine la progression de l’AFCD. Les chercheurs se concentreront sur des enzymes glycosylantes spécifiques et identifieront les protéines qu’elles modifient ainsi que leur impact sur le comportement tumoral et l’évasion immunitaire. En découvrant les mécanismes de glycosylation spécifiques au sous-type, le projet vise à révéler de nouveaux biomarqueurs et de nouvelles cibles thérapeutiques afin d’améliorer la détection précoce et les stratégies de traitement de l’AFCD.

Objectif

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive cancer type, with a 5-year survival rate of just 10%. This is primarily due to late-stage diagnosis and resistance to current treatments. Therefore, understanding the molecular mechanisms driving PDAC progression is critical for developing more effective diagnostic and therapeutic approaches.
Glycosylation, one of the most prevalent post-translational modification, is fundamentally altered in PDAC. The two clinically significant subtypes present in PDAC, called Classical and Basal, have distinct glycosylation profiles that affect tumor cell biology and its interactions with the microenvironment and immune system. Despite its importance, the particular mechanisms involved are poorly understood.
This project aims to elucidate how glycosylation drives PDAC, by characterizing the glycoproteins involved in different subtypes. We are particularly focus in the glycosylation enzymes GalNAc-T1 and GalNAc-T3, which have fundamental yet distinct roles in Classical and Basal cancer cells. However, their substrate proteins and underlying mechanisms remain largely unknown. Using bump-and-hole engineering, combined with click chemistry and mass spectrometry, we will pinpoint the glycoprotein substrates and glycosylation sites modified by these isoenzymes, offering unparalleled insight into the roles of glycans in PDAC.
We will also characterize the biological functions of these glycoproteins through biochemical, cell biology, and immunological methods. By revealing how these glycoproteins influence cancer cell biology and immune recognition, this project could uncover novel mechanisms involved in PDAC progression, which can lead to the identification of new biomarkers or therapeutic targets, potentially improving patient outcomes.