Loss of HNF1b drives pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) initiation
BackgroundIntraductal papillary mucinous neoplasms (IPMNs) are clinically detectable precursors of pancreatic adenocarcinoma, yet the mechanisms initiating their development remain poorly defined. Although KRAS mutations are highly frequent in human IPMNs, KRAS activation in pancreatic ductal cells alone fails to recapitulate IPMN development in murine models, indicating that additional tumor-suppressive mechanisms must be overcome. ObjectiveThe objective was to determine whether loss of the transcription factor HNF1B predisposes to initiation of IPMN. DesignWe assessed HNF1B nuclear expression and promoter methylation in resected human IPMN specimens. To model IPMN initiation, we generated mice with ductal-specific inactivation of Hnf1b, alone or combined with KRASG12D. Ductal organoids and RNA-sequencing were used to investigate molecular mechanisms. Transcriptomic analyses were also performed on human IPMN surgical specimens. MRI from germline HNF1B mutation/deletion carriers was re-evaluated for IPMN prevalence. ResultsHuman IPMNs showed loss of HNF1B by immunochemistry, with enrichment to promoter methylation that increased with dysplasia grade. The KHC model recapitulated the key features of IPMN development including ductal dilation, high proliferation, papillary architecture and mucin production. Loss of Hnf1b together with Kras activation induced loss of primary cilia, cellular reprogramming and engaged oncogenic YAP and Wnt/{beta}-catenin signaling, similar to human IPMNs. Moreover, germline HNF1B carriers exhibited a markedly increased prevalence of branch-duct IPMN. ConclusionHNF1B functions as a tumor-suppressive gatekeeper of pancreatic ductal cells. These findings highlight HNF1B inactivation as a potential biomarker and therapeutic entry point for early interception of IPMN-driven pancreatic cancer. They also have implications for the surveillance of HNF1B-syndrome.