MultiPan · A Multi-omics Approach To Decode Epigenetic Lesions In Pancreatic Cancer Development

A Multi-omics Approach To Decode Epigenetic Lesions In Pancreatic Cancer Development

Epigenetic mechanisms enable cells to achieve distinct phenotypes while sharing the same genetic information through precise regulation of genome accessibility and gene expression. Pancreatic Ductal Adenocarcinoma (PDAC), the most common form of pancreatic cancer, represents an abysmal disease with a 5-year survival rate of only ~8%. The mutation signature of the disease it is well known (it includes KRAS, TP53, SMAD4 and CDKN2A) and it has been recently shown that epigenetic mechanisms are key in defining the aggressiveness of PDAC since the early stages of the disease. To elucidate the molecular mechanisms of diseases, it is key to use models that accurately recapitulate the sequence of events leading to the malignancy. 3D cultures (such as spheroids or organoids) emerged as a reliable system for in vitro studies and, in case of PDAC-derived organoids, it was shown that when orthotopically transplanted into mice they gave rise to tumours recapitulating the morphology, metabolism and heterogeneous histology of the parental tissue. For this action we made use of the healthy, PDAC patient-derived and Cas9-engineered organoids to carry out the first multi-omics (single-cell RNA and ATAC sequencing) study in these biological entities at single cell resolution, to provide new insights into the heterogeneity of the epigenetic mechanisms driving cancer evolution. Therefore, the major goal of the proposed project is to perform a systematic survey and analysis of epigenetic lesions occurring in PDAC, as to generate a novel map of epimutations responsible for the growth of cancer cells and create an resource for future drug development studies.

Data: CORDIS, © European Union