Project description
Glycosylation and immune evasion in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is known for its resistance to treatment and a highly immunosuppressive tumour microenvironment. Recent evidence underscores the role of sugar moieties on proteins in helping tumours evade immune attack. Cancer cells often change the glyco-codes on their surface proteins and, following recognition by glycan-binding proteins (GBPs) on immune cells, they suppress immune responses. With the support of Marie Skłodowska-Curie Actions programme, the DiscoverableTumor project aims to understand how common PDAC mutations, especially in the KRAS oncogene, influence glycan structures and their interaction with GBPs. The discovery of new oncogene-driven immune evasion mechanisms in PDAC may fuel the development of promising therapeutic strategies for this aggressive disease.
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine oncology prostate cancer
- medical and health sciences basic medicine immunology
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences biochemistry biomolecules carbohydrates
- medical and health sciences clinical medicine oncology pancreatic cancer
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2024-PF-01
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28006 Madrid
Spain
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