Hes1 is essential in proliferating ductal cell-mediated development of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is frequently driven by aberrant KRAS activation and develops in the liver with chronic inflammation. Although the Notch signaling pathway is critically involved in ICC development, detailed mechanisms of Notch-driven ICC development are still unknown. Here we use mice whose Notch signaling is genetically engineered to show that the Notch signaling pathway, specifically the Notch/Hes1 axis, plays an essential role in expanding ductular cells in the liver with chronic inflammation or oncogenic Kras activation. Activation of Notch1 enhanced the development of proliferating ductal cells (PDC) in injured livers while depletion of Hes1 led to suppression. In correlation with PDC expansion, ICC development was also regulated by the Notch/Hes1 axis and suppressed by Hes1 depletion. Lineage-tracing experiments using EpcamcreERT2 mice further confirmed that Hes1 plays a critical role in the induction of PDC and that ICC could originate from PDC. Analysis of human ICC specimens showed PDC in non-neoplastic background tissues, confirming HES1 expression in both PDC and ICC tumor cells. Our findings provide novel direct experimental evidence that Hes1 plays an essential role in the development of ICC via PDC.