Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver.
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.
Benhamouche
Samira
S
Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, MA 02129, USA.
Curto
Marcello
M
Saotome
Ichiko
I
Gladden
Andrew B
AB
Liu
Ching-Hui
CH
Giovannini
Marco
M
McClatchey
Andrea I
AI
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000503:physiopathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000235:genetics / Q000503:physiopathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006529:Hepatomegaly / Q000235:genetics / Q000503:physiopathology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000503:physiopathology*; D008113:Liver Neoplasms / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D016518:Neurofibromatosis 2 / Q000235:genetics; D025581:Neurofibromin 2 / Q000235:genetics* / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D066246:ErbB Receptors