NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocytereprogramming into intrahepatic cholangiocarcinoma

Hu, S.; Molina, L. M.; Tao, J.; Liu, S.; Hassan, M.; Singh, S.; Poddar, M.; Bell, A.; Sia, D.; Oertel, M.; Raeman, R.; Nejak-Bowen, K.; Singhi, A.; Luo, J.; Monga, S. P.; Ko, S.

doi:10.1101/2020.12.03.410993

bioRxiv · 10.1101/2020.12.03.410993

NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocytereprogramming into intrahepatic cholangiocarcinoma

Hu, S.·Molina, L. M.·Tao, J.·Liu, S.·Hassan, M.·Singh, S.·Poddar, M.·Bell, A.·Sia, D.·Oertel, M.·Raeman, R.·Nejak-Bowen, K.·Singhi, A.·Luo, J.·Monga, S. P.·Ko, S.

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Abstract

Intrahepatic cholangiocarcinoma (ICC), a disease of poor prognosis, has increased in incidence. It is challenging to treat due to intra- and inter-tumoral heterogeneity, which in part is attributed to diverse cellular origin. Indeed, co-expression of AKT and NICD in hepatocytes (HCs) yielded ICC, with similarity to proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD regulated SOX9 and YAP1 during ICC development. Yap1 deletion or TEAD inhibition impaired HC-to-biliary epithelial cell (BEC) reprogramming and ICC proliferation; Sox9 loss repressed tumor growth; and Yap1-Sox9 combined loss abolished ICC development in AKT-NICD model. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directed HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch-dependent HC-to-ICC development, and DNMT1 re-expression restored ICC development following TEAD repression. Coexpression of DNMT1 with AKT was sufficient to induce hepatic tumor development including ICC. Thus, we have identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-driven ICC development. SIGNIFICANCEWe evaluated the clinical relevance of hepatocyte-driven ICC model and revealed critical but distinct roles of YAP1 and SOX9 in AKT-NICD-driven hepatocyte-derived ICC. We also identified NOTCH-YAP1/TEAD-DNMT1 axis as a critical driver for hepatocyte-to-ICC reprogramming, which might have biological and therapeutic implications in ICC subsets.

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Hu, S., Molina, L. M., Tao, J., Liu, S., Hassan, M., Singh, S., Poddar, M., Bell, A., Sia, D., Oertel, M., Raeman, R., Nejak-Bowen, K., Singhi, A., Luo, J., Monga, S. P., Ko, S.. 2020-12-04. NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocytereprogramming into intrahepatic cholangiocarcinoma. https://doi.org/10.1101/2020.12.03.410993

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