Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver
- Samira Benhamouche1,3,
- Marcello Curto1,3,
- Ichiko Saotome1,
- Andrew B. Gladden1,
- Ching-Hui Liu1,
- Marco Giovannini2 and
- Andrea I. McClatchey1,4
- 1Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
- 2Center for Neural Tumor Research, House Ear Institute, Los Angeles California 90057, USA
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↵3 These authors contributed equally to this work.
Abstract
The molecular signals that control the maintenance and activation of liver stem/progenitor cells are poorly understood, and the role of liver progenitor cells in hepatic tumorigenesis is unclear. We report here that liver-specific deletion of the neurofibromatosis type 2 (Nf2) tumor suppressor gene in the developing or adult mouse specifically yields a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma, suggesting that Nf2−/− progenitors can be a cell of origin for these tumors. Despite the suggested link between Nf2 and the Hpo/Wts/Yki signaling pathway in Drosophila, and recent studies linking the corresponding Mst/Lats/Yap pathway to mammalian liver tumorigenesis, our molecular studies suggest that Merlin is not a major regulator of YAP in liver progenitors, and that the overproliferation of Nf2−/− liver progenitors is instead driven by aberrant epidermal growth factor receptor (EGFR) activity. Indeed, pharmacologic inhibition of EGFR blocks the proliferation of Nf2−/− liver progenitors in vitro and in vivo, consistent with recent studies indicating that the Nf2-encoded protein Merlin can control the abundance and signaling of membrane receptors such as EGFR. Together, our findings uncover a critical role for Nf2/Merlin in controlling homeostasis of the liver stem cell niche.
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Footnotes
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↵4 Corresponding author.
E-MAIL mcclatch{at}helix.mgh.harvard.edu; FAX (617) 726-7808.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1938710.
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Supplemental material is available at http://www.genesdev.org.
- Received April 17, 2010.
- Accepted June 18, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press