Project Details
Projekt
Inducing therapeutic vulnerabilities in patient-derived PDAC models by targeting the metabolome-to-3D chromatin axis
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426671079
During the 1st funding period, we exploited our expanding cohort of pancreatic cancer (PDAC) patient-derived organoids (PDOs) to uncover their dependency on metabolism-guided genome dynamics. We were able to stratify this cohort on the basis of high/low expression of a key chromatin-binding factor, HMGB2, the abundance of which correlates with the proliferative potency and metabolic state of patient-derived PDOs. HMGB2 can be targeted pharmacologically using a novel senogenic agent, ICM, which induces a more glycolytic state in HMGB2high cells especially. ICM-treated PDOs can therefore be efficiently targeted by co-inhibition of glycolysis using the PFKFB3 inhibitor KAN0438757. A combination of genomics and functional assays in cell lines, PDOs, and mouse models, showed that our approach identified a pervasive, new, and druggable vulnerability in PDAC that targets the metabolome-to-chromatin axis. Given that pharmacological alleviation of HMGB2 from PDAC cell nuclei induces cell senescence, and that glycolytic inhibition will alter histone modifications globally, PDAC entities subjected to such dual treatment become less proliferative and likely more susceptible to chemotherapy. In the 2nd funding period, we will test this postulation via cutting-edge genomics (including 3D, spatial, and single-cell genomics) in PDOs and mouse models of the CRU5002 cohort. We plan to map the changing 3D chromatin landscape of metabolome-dependent enhancers and the altered metabolome of PDAC PDOs treated with senogenic drugs pushing tumors towards glycolysis-dependent phenotypes and combining metabolome-altering inhibitors, while also obtaining a single-cell and spatial understanding of PDAC tumors under combinatorial treatment in vivo. For this, we will work with CP1 for access to paired primary tumor- and metastasis-derived PDOs and for high-throughput testing of FDA-approved drugs with our ICM and KAN0438757 agents, as well as with CP2 for further genomic characterization of PDOs and clinical samples. We will also engage with SP1 for secretome analysis of ARID1A-deficient tumors and with SP4 for dissecting the consequences of GSK3β-signaling on PFKFB3 targeting. Together with SP8 we will explore the impact of interfering with glycolysis upon increased RNAPII-mediated transcriptional elongation upon PP2A inhibition. Taken together, this natural continuation of our initial CRU5002 project is bound to provide new mechanistic as well as clinically relevant insights into PDAC biology.
DFG Programme
Clinical Research Units
