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

Descripción del proyecto

La glicosilación en el adenocarcinoma ductal pancreático

La glicosilación es una modificación postranscripcional común en proteínas y lípidos y tiene una gran importancia en la regulación de la función celular y las respuestas inmunitarias. El adenocarcinoma ductal pancreático (ADP o PDAC, por sus siglas en inglés) presenta diferentes patrones de glicosilación. En el proyecto GlycoPDAC, financiado por las acciones Marie Skłodowska-Curie, se investigará cómo la glicosilación favorece la evolución del ADP. Los investigadores se centrarán en enzimas glicosilantes específicas e identificarán qué proteínas modifican, así como su efecto en el comportamiento tumoral y la evasión inmunitaria. Al descubrir mecanismos de glicosilación específicos de cada subtipo, el equipo del proyecto se propone revelar nuevos biomarcadores y dianas terapéuticas para mejorar la detección temprana y el tratamiento del ADP.

Objetivo

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.