Objective
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.
Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
28006 Madrid
Spain