Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors

  1. Andrea I. McClatchey,
  2. Ichiko Saotome,
  3. Kim Mercer,
  4. Denise Crowley,
  5. James F. Gusella,
  6. Roderick T. Bronson, and
  7. Tyler Jacks
  1. Department of Biology and the Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 USA; U.S. Department of Agriculture Human Nutrition Research Center on Aging, Department of Pathology, School of Veterinary Medicine, Tufts University, Boston, Massachusetts 02111 USA; Molecular Neurogenetics Unit, Massachusetts General Hospital East and Harvard Medical School, Charlestown, Massachusetts 02129 USA

Abstract

A role for the membrane/cytoskeleton interface in the development and progression of cancer is established, yet poorly understood. The neurofibromatosis type II (NF2) tumor suppressor gene encodes a member of the ezrin/radixin/moesin (ERM) family of membrane/cytoskeleton linker proteins thought to be important for cell adhesion and motility. We report that in contrast to the narrow spectrum of benign tumors in human NF2 patients, Nf2heterozygous mice develop a variety of malignant tumors. Using the fact that Nf2 is linked to the p53 tumor suppressor locus in the mouse we have also investigated the effects of genetic linkage of cancer-predisposing mutations on tumorigenesis and examined the genetic pathway to tumor formation involving Nf2 loss. Importantly, we observed a very high rate of metastasis associated with Nf2deficiency, with or without loss of p53 function, and we provide experimental evidence supporting a role for Nf2 loss in metastatic potential. Together, our results suggest an important role for the NF2 tumor suppressor, and perhaps the ERM family in tumor formation and metastasis.

Keywords

Footnotes

  • Corresponding author. Present address: Massachusetts General Hospital Cancer Center and Harvard Medical School Department of Pathology, Charlestown, Massachusetts 02129 USA.

  • E-MAIL mcclatch{at}helix.mgh.harvard.edu; FAX (617) 726-7808.

    • Received January 20, 1998.
    • Accepted February 25, 1998.
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