Objective Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia 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). The transcriptional regulators required to initiate ADM are unknown, but need to be identified to characterise the regulatory networks that drive ADM. In this study, 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 was investigated.
Design Expression of HNF6 and Sox9 was measured by immunostaining in normal and diseased human pancreas. The function of the factors was 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 was ectopically induced in acinar cells in human ADM as well as in mouse models of ADM. HNF6 and, to a lesser extent, Sox9 were 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 treatment in cases when ADM may lead to cancer. This work also shows that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.
- transcription factors
- molecular oncology
- diabetes mellitus
- colon carcinogenesis
- stem cells
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↵* PPP, AS and AG contributed equally to the present work.
Funding This work was supported by grants from the Fondation contre le Cancer and from the EU FP7 (Marie Curie Initial Training Network BOLD) to FPL and AG, from the Juvenile Diabetes Research Foundation to XX, from an EFSD/MSD award and from the EU FP6 to HH, from the NIH (CA124586) to SFK and from the Université catholique de Louvain and the Centre du Cancer to PJ. Generation of the anti-HNF6 antibody was supported by BCBC grant U01DK072473 to Ole D Madsen (as PI of Antibody Core Facility). VR is supported by a FRSM grant from the FRS-FNRS. P-PP is a postdoctoral researcher at the FRS-FNRS (Belgium). LB and PJ are research associates at the FRS-FNRS.
Competing interests None.
Patient consent Obtained.
Ethics approval All animal experiments were performed with the approval of the welfare committee of the institution.
Provenance and peer review Not commissioned; externally peer reviewed.