SP1: Understanding and exploiting molecular and cellular reprogramming in to EZH2 inhibition in PDAC

In SP1, the Hauschild and Hessmann groups will combine their expertise in bioinformatics, machine learning, as well as advanced AI methods and GI cancer modelling and epigenetic targeting, respectively, to dissect the molecular underpinnings and the therapeutic consequences of EZH2-inhibition (EZH2i)-induced adaptation in PDAC. In the canonical Polycomb-Repressor-Complex 2 pathway, EZH2 modifies the chromatin landscape by trimethylation of the histone 3 residue lysine 27 (H3K27me3) to foster tumor cell proliferation, stemness traits, and aggressiveness. However, despite its oncogenic activities, pharmacological interference with EZH2 activity and expression is not sufficient to combat PDAC, but induces adaptation of the epithelial and microenvironmental tumor compartment. However, the molecular and cellular characteristics and the therapeutic consequences of EZH2i-induced adaptation remain elusive and hence will be addressed by the SP1 team. To this end, the PhD-candidate of the first cohort (Hessmann lab) will generate orthotopic transplantation models utilizing a repertoire of primary PDAC cells, and will study the consequences of EZH2i at the phenotypic (e.g. growth dynamics, metastasis) and molecular level. These studies will involve scRNA- and ChIP-seq technology to explore EZH2i-induced cellular shifts as well as alterations of the transcriptional program and the chromatin landscape. Complementing this work, the MD-candidate of the first cohort (Hauschild group) will utilize different therapeutic strategies targeting EZH2 and will perform transcriptome analyses to distinguish between canonical and non-canonical EZH2i-mediated transcriptional adaptation processes. The PhD-candidate of the second cohort (Hauschild group) will focus on the development and integration of systems medicine-based computational approaches and will apply them to the comprehensive datasets accomplished by the first cohort of SP1 doctoral candidates in order to identify cells with/without EZH2i-induced shifts. Subsequently, he/she will employ explainable AI methods to identify signatures hinting towards therapeutic vulnerabilities of the EZH2i-induced adaptive state and will explore in-silico findings with regard to their implication on tumor progression and therapeutic susceptibility by using focused CRISPR-Cas9 and drug screens. The MD-candidate of the second cohort (Hessmann lab) will prioritize the most promising therapeutic strategies exploiting EZH2i-installed adaptation in PDAC organoid models and will translate them to therapeutic strategies in vivo. Together, in an interdisciplinary approach, the SP1 team has the unique chance to develop a tailored EZH2i-based combinatory therapeutic strategy for the treatment of pancreatic cancer patients.