Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

Barthet, V. J.A. et al. (2021) Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver. Science Advances, 7(23), eabf9141. (doi: 10.1126/sciadv.abf9141) (PMID:34088666)

Abstract

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research U.K. core funding to the Beatson Institute (A17196) and core funding to K.M.R. (A22903). M.M. and T.G.B. were funded by the Welcome Trust (grant number: WT107492Z).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: O'Prey, Mr James and Nixon, Mr Colin and May, Dr Steph and Nössing, Christoph and Long, Dr Jaclyn and Baudot, Dr Alice and Kiourtis, Christos and Barthet, Valentin and Bird, Dr Thomas and Ryan, Professor Kevin and Brucoli, Martina
• Authors: Barthet, V. J.A., Brucoli, M., Ladds, M. J.G.W., Nössing, C., Kiourtis, C., Baudot, A. D., O'Prey, J., Zunino, B., Müller, M., May, S., Nixon, C., Long, J. S., Bird, T. G., and Ryan, K. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Science Advances
• Publisher: American Association for the Advancement of Science
• ISSN: 2375-2548
• ISSN (Online): 2375-2548
• Published Online: 04 June 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Science Advances 7(23): eabf9141
• Publisher Policy: Reproduced under a Creative Commons License