Loss of HNF1b drives pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) initiation
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Background & Aims
Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) are precancerous lesions characterized by dilated and dysplastic ducts. The molecular mechanisms underlying their initiation and progression to pancreatic adenocarcinoma are not fully elucidated. While Kras mutations are highly frequent in IPMN, activating Kras in ductal cells is not sufficient to trigger IPMN formation in mice. Here, we explore whether loss of HNF1B, a transcription factor that notably plays a pivotal role in pancreatic development, predisposes to IPMN formation.
Methods
We generated a mouse model combining Hnf1b inactivation and an activating KRAS mutation in pancreatic ducts (KHC). The impact of HNF1B loss on IPMN development was investigated via morphological and transcriptomic analysis in vivo and in organoids, as well as in human tissue and patient cohorts.
Results
The KHC model recapitulates the development of IPMN, characterized by ductal dilation, high proliferation, papillary architecture and mucus production. Inactivation of Hnf1b in combination with activated KRAS drives IPMN by promoting primary cilia loss and specific oncogenic pathways such as YAP and Wnt pathways, showing the pivotal role of ciliary disruption and the key molecular alterations in IPMN initiation. Hnf1b -deficient pancreatic ductal cells enter a pretumoral state marked by genomic instability and early pathway dysregulation such as PI3K-AKT pathway up-regulation prior to dysplasia. Importantly, these data correlate with human IPMN, revealing HNF1B silencing via promoter methylation and high prevalence of IPMNs in patients harboring HNF1B mutations.
Conclusion
These findings identify HNF1B as a tumor suppressor in the initiation of IPMN and reveal key molecular mechanisms underlying the early stages of this neoplastic process.
