3D genome reorganization during induced senescence in pancreatic cancer – insights from analysis of single chromatin fibers

• Applicant: Professor Dr. Argyris Papantonis
• Subject Area: General Genetics and Functional Genome Biology ; Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563840778

Uncontrolled proliferation together with mechanisms to evade natural senescence and programmed cell death are defining features allowing cancer to thrive. Our previous work showed that early commitment to the fate of senescence is controlled by the depletion of the HMGB2 protein from human cell nuclei. This triggers a dramatic rewiring of genome architecture contributing to replicative arrest. HMGB proteins are depleted in aging tissues but at the same time significantly overexpressed in many cancer types, including one of the most deadly: pancreatic adenocarcinomas. We now have evidence that HMGB2 overexpression is governed by the SOX4 transcription factor, the manipulation of which leads to differential responses of pancreatic cancer cells to therapy. Based on this new evidence, we propose investigating how such therapy responses unfold in pancreatic adenocarcinoma (PDAC) organoids and 'SOX4-degron' cell lines via changes to the cells’ epigenome and 3D genome architecture. To achieve this, we will take advantage of an existing collection of PDAC patient-derived organoids with full genetic and clinical annotations from the Papantonis team. We will first characterize transcriptional and epigenomic changes induced by the presence or absence of an active SOX4-HMGB2 axis modulating senescence. Second, we will revisit these transcriptional and epigenomic responses following treatment with selected FDA-approved drugs that already showed differential effects in our recent screen. Third, based on this data, we will define a set of genomic loci encompassing 5-10% of the genome for further multi-modal analysis at the level of single chromatin fibers in cells with high or suppressed SOX4 levels aiming at generating a database with structural genomic biomarkers of potential diagnostic value. For this purpose, we will employ a novel method established by the Gdula team and based on long-read sequencing, which allows for the simultaneous detection of mutations, DANN methylation, structural variation and 3D chromatin interactions from the same chromatin fiber. Collectively, our project will shed light on how PDAC evades or even reverses the inherent program of cellular senescence to support progression of this detrimental malignancy and provide a set of biomarkers with clinical potential.

• DFG Programme: Research Grants
• International Connection: Poland
• Cooperation Partner: Dr. Michal Gdula