Our data show a direct and hitherto unknown convergence of the canonical Wnt signaling on the HNF4alpha-driven transcription providing evidences of a mechanism controlling liver zonated gene expression.

Objective Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia (PanIN) and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). Transcriptional regulators required to initiate ADM still remain unknown, yet need to be identified to characterise the regulatory networks that drive ADM. Here we investigate the role of the ductal transcription factors Hepatocyte Nuclear Factor 6 (HNF6, also known as Onecut1)and SRY-related HMG box factor 9 (Sox9) in ADM. Design Expression of HNF6 and Sox9 is measured by immunostaining in normal and diseased human pancreas. The function of the factors is tested in cultured cells and in mouse models of ADM by a combination of gain- and loss-of-function experiments. Results Expression of HNF6 and Sox9 is ectopically induced in acinar cells in human ADM, as well as in mouse models of ADM. We show that these factors are required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity, and for activation of ductal genes in metaplastic acinar cells. Conclusions HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive therapy in cases when ADM may lead to cancer. Our work also highlights that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.

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