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)

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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:Long, Dr Jaclyn and Baudot, Dr Alice and Barthet, Valentin and Bird, Dr Thomas and Ryan, Professor Kevin and Brucoli, Martina and O'Prey, Mr James and Nixon, Mr Colin and Nössing, Christoph and Kiourtis, Christos
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 > Institute 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

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