Pancreatic ductal adenocarcinoma (PDAC) is among the worst diagnoses in medicine, with a 5-year survival rate of 4%, in part because most cases are detected well after metastasis has occurred. Models of PDAC evolutionary history have emerged from DNA sequencing studies of metastases and primary tumours and reveal a progressive elaboration of malignant and metastatic cells that takes 20 or more years.1 Interestingly, at least half of this time is spent in a premalignant state, termed pancreatic intraepithelial neoplasia (PanIN), suggesting that a decade-long window exists for prediction, detection and prevention of pancreatic cancer. Two papers published in Gut use mouse models to derive new insights into human-relevant genetic and environmental influences that drive PanIN formation and progression, and highlight the importance of differentiation as a barrier to tumourigenesis.2 ,3

The first genetic event on the road to invasive pancreatic cancer is mutational activation of KRAS, which occurs in the earliest precancerous PanIN-1 lesions. Experimental research on PDAC initiation was transformed 10 years ago, when a mouse model of PanIN–PDAC progression was developed based on pancreas-specific, Cre recombinase-mediated activation of endogenous mouse Kras.4 This model has been used to validate and dissect both rare genetic risk factors for PDAC, such as Ink4a/Arf deficiency,5 and environmental risk factors …