Project description
Decoding genomic heterogeneity in cancer
Cancer cells are characterised by high frequency of mutations and chromosomal rearrangements that lead to genetic diversity and heterogeneity. Recent evidence suggests that complex genomic rearrangements (CGRs) may drive the evolution of pancreatic ductal adenocarcinoma (PDAC), the most common and lethal form of pancreatic cancer. Funded by the Marie Skłodowska-Curie Actions progamme, the EVO-PDAC project aims to clarify the role of CGRs, structural variants and point mutations in PDAC progression. Using cutting-edge techniques, researchers will create multiomics atlases of PDAC at different stages. Results will help researchers understand PDAC evolution and the emergence of intratumour heterogeneity.
Objective
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, a disease with a dismal prognosis. PDAC has an especially high tendency of quickly metastasizing and becoming resistant to therapy, and the mechanisms by which this occurs are largely unknown. Recent evidence suggests that saltatory or burst-like evolution mediated by complex genomic rearrangements (CGRs) may be especially relevant in PDAC, altering multiple cancer genes in a single event. However, quantifying CGRs requires specialized techniques (such as Strand-Seq), and therefore the relative importance of CGRs, simple structural variants, and point mutations in PDAC evolution remains unclear. In this project, we will use a genetically engineered mouse model (GEMM) that develops de novo PDAC to longitudinally track PDAC evolution by single-cell and spatial multi-omic methods, using Strand-Seq to accurately detect CGRs. Thus, we aim to create longitudinal single-cell and spatial multi-omic atlases of PDAC at three key evolutionary steps: pre-cancer, therapy-naive PDAC, and post-therapy PDAC. In addition, we will compare our atlases to human PDAC data from the Spatial And Temporal Resolution of Intratumoral Heterogeneity in 3 hard-to-treat Cancers (SATURN3) Consortium. In this way, we will model PDAC evolution at various time points, quantifying the relative importance of gradual vs saltatory evolution and determining how evolvability changes over time. Moreover, we will infer the role of selective pressures from the tumor microenvironment (e.g. immune cells and cancer-associated fibroblasts) in shaping PDAC evolution. Finally, we will explore how all these factors interact with the high intratumoral heterogeneity observed in PDAC. Overall, this project will answer long-standing questions about the evolutionary dynamics of PDAC.
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.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesclinical medicineoncologyprostate cancer
- natural sciencesbiological sciencesgeneticsmutation
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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
69117 Heidelberg
Germany