MICE HETEROZYGOUS FOR A MUTATION AT THE NF2 TUMOR-SUPPRESSOR LOCUS DEVELOP A RANGE OF HIGHLY METASTATIC TUMORS

A role for the membrane/cytoskeleton interface in the development and progression of cancer is established, yet poorly understood. The neuro fibromatosis type II (NF2) turner 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 re port that in contrast to the narrow spectrum of benign tumors in human NF2 patients, Nf2 heterozygous mice develop a variety of malignant tu mors. Using the fact that Nf2 is linked to the p53 tumor suppressor lo cus in the mouse we have also investigated the effects of genetic link age of cancer-predisposing mutations on tumorigenesis and examined the genetic pathway to tumor formation involving Nf2 loss. Importantly, w e observed a very high rate of metastasis associated with Nf2 deficien cy, with or without loss of p53 function, and we provide experimental evidence supporting a role for Nf2 loss in metastatic potential. Toget her, our results suggest an important role for the NF2 tumor suppresso r, and perhaps the ERM family in tumor formation and metastasis.