Oncogene-driven immunosuppression via glyco-immune checkpoint modulation in pancreatic ductal adenocarcinoma.

Descripción del proyecto

La glicosilación y la evasión inmunitaria en el cáncer de páncreas

El adenocarcinoma ductal pancreático (ADP) se caracteriza por su resistencia al tratamiento y por un microambiente tumoral altamente inmunosupresor. Nuevas pruebas destacan el papel de los hidratos de carbono o glicanos en las proteínas para ayudar a los tumores a evadir el sistema inmunitario. Las células cancerosas suelen modificar los patrones de glicosilación en las proteínas de su superficie y, tras ser reconocidas por proteínas de unión a glicanos (GBP, por sus siglas en inglés) en las células inmunitarias, suprimen las respuestas inmunitarias. El proyecto DiscoverableTumor, financiado por las acciones Marie Skłodowska-Curie, tiene como objetivo dilucidar cómo las mutaciones comunes del ADP, sobre todo en el oncogén KRAS, influyen en las estructuras de los glicanos y su interacción con las GBP. El descubrimiento de nuevos mecanismos de evasión inmunitaria promovidos por oncogenes en el ADP podría favorecer el desarrollo de estrategias terapéuticas prometedoras para esta neoplasia maligna.

Objetivo

Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive tumors, ranking as the third leading cause of cancer-related death. Glycosylation has emerged as a critical regulatory mechanism contributing to tumor progression and immunosuppression, a hallmark of PDAC tumor microenvironment (TME). Recent studies have shown that tumor immune evasion programs can be facilitated by the activation of immunosuppressive glyco-immune checkpoints (GICs), governed by interactions between cell-surface glycans and glycan-binding proteins (GBPs). While oncogene mutations are known to have immunosuppressive effects and impact protein glycosylation, their effect on GIC modulation remains unexplored. This project aims to investigate how oncogene mutations affect GBP-glycan interactions acting as GICs in PDAC, potentially identifying new therapeutic targets. To identify relevant GICs, I will examine how the most frequent KRAS oncogene mutations in PDAC affect glycosylation and GBP activity, leading to the creation of immunosuppressive functions. Using co-culture experiments with primary pancreatic duct epithelial cells and key TME cellular components, such as cancer-associated fibroblasts, as well as lymphoid and myeloid immune cells, I intend to uncover alterations in the cell surface glycome and changes in GBP binding activity that contribute to immunosuppressive pathways. I will employ unbiased glycan-targeted proximity labeling techniques to uncover novel oncogene-driven GBP-glycan axes and simultaneously analyze the activities of GBPs previously associated with cancer and immune evasion, such as galectins (galectins 1/3/9) and siglecs (particularly Siglecs 7/9/15). The findings will be validated using cellular and organoid models of PDAC to assess candidate GICs as therapeutic targets for this challenging disease.