First, we generated DRS and TRS models and developed novel non-genetic strategies to deliver site-specific recombinases to the pancreas via electroporation strategies as well as viral AAV based gene transfer for somatic gene targeting and CRISPR/Cas9 based genetic engineering in vivo. This opened new possibilities to investigate PDAC mechanistically in vivo and to identify novel cancer genes and therapeutic targets. To exploit the full potential of the DRS and TRS based PDAC models, we systematically investigated subpopulations of cells of the tumor microenvironment, which support tumor growth and developed systems to target cell subtypes, which are not precisely characterized by a single marker, but only by marker combinations. These results have been published in Nature Communications, Nature Protocols, Nature Reviews Cancer and EMBO Molecular Medicine.
Next, we applied our novel PDAC models to address therapeutic questions of high clinical relevance for PDAC patients. We used the models to 1) uncover evolutionary routes of PDAC development and understand their impact on tumor phenotypes (published in Nature, 2018), 2) identify cancer genes and candidate therapeutic targets in PDAC functionally (published in Cancer Discovery 2021, Gastroenterology 2021, Nature Communications 2016), 3) perform synthetic lethal CRISPR/Cas-based genetic loss and gain of function screens to identify genes which induce cancer cell death (unpublished), and to 4) show that the molecular makeup of the primary PDAC dictates if a cell in the tumor microenviroment promotes or restains tumor development. This indicates an extraordinary context specificity of PDAC stroma crosstalk, which is of fundamental relevance for establishing novel therapeutic strategies. Indeed, the combined targeting of PDAC cells and their immunosuppressive stroma sensitizes them to immunotherapy (published in Nature Cancer 2022).
Finally, we investigated primary and secondary resistance towards targeted PDAC therapies, which is a major clinical problem. We used our novel models and tools to uncover resistance at the genetic, epigenetic and transcriptional level and identified several pathways and modes of resistance, such as Myc amplification, which provide novel and unexpected vulnerabilities and opportunities for combination therapies (unpublished).
We exploited and disseminated our discoveries by various means, such as 1) exchange of models, technologies and data with collaborators nationally and internationally, 2) international scientific meetings and symposia, 3) educational programs in Germany and Europe, 4) seminars, workshops and international conferences in Munich, 5) national and international research societies for oncology and pancreas research, 6) publications, reviews, and overview articles in high profile journals, such as Nature Reviews Cancer, and 7) knowledge transfer and public relations via social media (e.g. Twitter channel with >350 followers, interviews in the German magazines, patient involvement, press releases and public events).
