Genome-wide surveys and functional analysis of pancreatic cancer metastasis drivers

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Metastasis is the major cause of death in pancreatic ductal adenocarcinoma (PDAC). International sequencing efforts on >800 human primaries gave comprehensive insights into PDAC genetics. In contrast, equivalent studies for “metastasis genetics” were not possible, largely because of a lack of metastatic tissue resources, particularly of treatment-naive ones. Another bottleneck is the scarcity of adequate experimental models recapitulating the multi-step nature of metastasis. As a consequence, the molecular basis of metastasis remains poorly understood. We developed unique resources and tools for metastasis research and propose to use them at three levels to systematically interrogate the molecular underpinnings of PDAC metastasis. We will first perform complementary genome-scale surveys for genes and pathways driving metastasis and metastatic organotropism. We will (i) sequence our unique, largely unpublished resource of 1200 metastatic mouse PDAC, (ii) will perform genome-wide in vivo metastasis screens using transposon tools and approaches, which we pioneered in mice, and (iii) will perturb the human metastasis transcriptome and epigenome. Second, we will validate newly discovered genes using human PDAC cohorts, and through functional studies in mice. We will deploy next-generation metastasis models based on advanced somatic genome engineering. They allow rapid functional studies at an organismal level, thus capturing the complexity of the metastatic cascade. Third, building on our recent discovery of two prototype PDAC metastasis drivers, we will perform in depth mechanistic studies to identify underlying molecular networks and vulnerabilities. This work will unravel - for the first time - comprehensive genetic and functional landscapes of PDAC metastasis. PACA-MET thus promises to uncover fundamental novel biological principles and identify therapeutic targets for one of biggest challenges in medicine.