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Pr. Dieter SAUR / Heterogeneity of Pancreatic Cancer – Implications for Future Therapies?
8 février 2019 @ 11:00 - 13:00
Pr. Dieter SAUR, TUM, Munich
Treatment resistance of pancreatic cancer (PDAC) depends on cancer cell intrinsic mechanisms and an immunosupressive tumor stroma that supports tumour growth. Mouse models have provided important insights into the evolution of this highly lethal tumour, but there are no models that allow secondary genetic manipulation of autochthonous tumours, the immune system or the metastatic host niche once the tumour has formed. We generated novel PDAC models that permit spatial and temporal control of gene expression and modelling of PDAC subtypes and their respective microenvironments. These tools provide unparalleled access to the native biology of cancer cells and their hosting stroma, and rigorous genetic validation of candidate therapeutic targets in autochthonous tumours and subtype specific drivers in the immune system. Using these models we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in PDAC, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest KrasMUT levels underlying aggressive undifferentiated phenotypes.