Cholangiocarcinomas can originate from hepatocytes in mice

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

Research output: Contribution to journalArticle

208 Citations (Scopus)

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

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Cholangiocarcinoma
Hepatocytes
Liver
Stem Cells
Epithelial Cells
Bile Ducts
Histology
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

Cholangiocarcinomas can originate from hepatocytes in mice. / Fan, Biao; Malato, Yann; Calvisi, Diego F.; Naqvi, Syed; Razumilava, Nataliya; Ribback, Silvia; Gores, Gregory James; Dombrowski, Frank; Evert, Matthias; Chen, Xin; Willenbring, Holger.

In: Journal of Clinical Investigation, Vol. 122, No. 8, 01.08.2012, p. 2911-2915.

Research output: Contribution to journalArticle

Fan, B, Malato, Y, Calvisi, DF, Naqvi, S, Razumilava, N, Ribback, S, Gores, GJ, Dombrowski, F, Evert, M, Chen, X & Willenbring, H 2012, 'Cholangiocarcinomas can originate from hepatocytes in mice', Journal of Clinical Investigation, vol. 122, no. 8, pp. 2911-2915. https://doi.org/10.1172/JCI63212
Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S et al. Cholangiocarcinomas can originate from hepatocytes in mice. Journal of Clinical Investigation. 2012 Aug 1;122(8):2911-2915. https://doi.org/10.1172/JCI63212
Fan, Biao ; Malato, Yann ; Calvisi, Diego F. ; Naqvi, Syed ; Razumilava, Nataliya ; Ribback, Silvia ; Gores, Gregory James ; Dombrowski, Frank ; Evert, Matthias ; Chen, Xin ; Willenbring, Holger. / Cholangiocarcinomas can originate from hepatocytes in mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 8. pp. 2911-2915.
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