Cholangiocarcinomas can originate from hepatocytes in mice

Biao Fan, Yann Malato, Diego F. Calvisi, Syed Naqvi, Nataliya Razumilava, Silvia Ribback, Gregory J. Gores, Frank Dombrowski, Matthias Evert, Xin Chen, Holger Willenbring

Research output: Contribution to journalArticle

244 Scopus citations

Abstract

Intrahepatic cholangiocarcinomas (ICCs) are primary liver tumors with a poor prognosis. The development of effective therapies has been hampered by a limited understanding of the biology of ICCs. Although ICCs exhibit heterogeneity in location, histology, and marker expression, they are currently thought to derive invariably from the cells lining the bile ducts, biliary epithelial cells (BECs), or liver progenitor cells (LPCs). Despite lack of experimental evidence establishing BECs or LPCs as the origin of ICCs, other liver cell types have not been considered. Here we show that ICCs can originate from fully differentiated hepatocytes. Using a mouse model of hepatocyte fate tracing, we found that activated NOTCH and AKT signaling cooperate to convert normal hepatocytes into biliary cells that act as precursors of rapidly progressing, lethal ICCs. Our findings suggest a previously overlooked mechanism of human ICC formation that may be targetable for anti-ICC therapy.

Original languageEnglish (US)
Pages (from-to)2911-2915
Number of pages5
JournalJournal of Clinical Investigation
Volume122
Issue number8
DOIs
StatePublished - Aug 1 2012

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Cholangiocarcinomas can originate from hepatocytes in mice'. Together they form a unique fingerprint.

  • Cite this

    Fan, B., Malato, Y., Calvisi, D. F., Naqvi, S., Razumilava, N., Ribback, S., Gores, G. J., Dombrowski, F., Evert, M., Chen, X., & Willenbring, H. (2012). Cholangiocarcinomas can originate from hepatocytes in mice. Journal of Clinical Investigation, 122(8), 2911-2915. https://doi.org/10.1172/JCI63212