Defining and targeting subtype specific inflammatory drivers in pancreatic cancer

• Applicants: Professor Dr. Dieter Saur; Professor Dr. Marc Schmidt-Supprian; Professor Dr. Fabian Theis
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515571394

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and heterogeneous cancer, which is remarkably resistant to chemo- and immunotherapies and with a 10-year-survival rate of ~1% almost invariably fatal. The molecular and cellular mechanisms of inflammatory signaling pathways that drive PDAC progression are poorly defined. In the past years, we characterized how defined genetic drivers and gene-dosage variation shape the inflammatory tumor microenvironment (TME) in PDAC. We uncovered critical cancer-mediated subtype-specific TME instruction in Kras-mutant tumors, which were reflected in different therapeutic responses. Based on these finding, we will pursue three major aims: 1) Systematic analysis of TME heterogeneity in its anatomical context 2) Identifying and targeting subtype-specific tumor–host interaction and communication 3) Improving therapeutic targeting of PDAC subtypes by TME modulation In aim 1, we will dissect subtype-specific TME composition by single cell technologies, complementing unique tumor-TME transcriptomes with their T- and B-cell receptor repertoires to characterize clonal dynamics of infiltrating lymphocytes. Moreover, we will integrate these approaches by phenotyping critical immune and tumor proteins through cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). Cell-type-specific labeling and mass spectrometry-based proteomics will allow an unbiased determination of in situ immune and cancer global proteomes. These datasets will be integrated with spatial transcriptomics, histology and multi-parameter immunofluorescence to yield precise information regarding the localization and immediate cellular interactions in PDAC. Bioinformatic data integration will uncover cellular communication networks in tumor subtypes, and to identify putative drivers of such interactions. In aim 2 we will make use of co-culture systems of PDAC subtypes with one or more specific immune cell-types as well as in vivo models to functionalize basal and drug perturbed cancer-TME communication networks. Advanced bioinformatic prediction of cellular responses to perturbations based on established comparisons between basal and perturbed settings will empower our studies to test causal hypotheses on TME dynamics. Critical binary interactions or transcriptional hubs regulating cancer-TME communication will then be investigated through genetic ablation in vitro and in vivo. In aim 3 we will identify PDAC vulnerabilities in pharmacological and genetic screens. This, together with results from aims 1 and 2, will yield candidates for new (immune modulatory) combination therapies, which we will test in vivo.

• DFG Programme: Research Grants