Andrea I. McClatchey


Department of Pathology
Massachusetts General Hospital Cancer Center
Building 149, 13th Street, Room 7406
Charlestown, MA 02129
Tel: (617) 726-5648
Fax: (617) 726-7808
Email: mcclatch@helix.mgh.harvard.edu
Web Page: The McClatchey Lab Page
4 postdoctoral fellows, 2 graduate students


We are interested in the role of the membrane:cytoskeleton interface in cancer development and progression. Our studies are focused on the NF2 tumor suppressor, Merlin and its family members, the ERM proteins (Ezrin, Radixin and Moesin), which localize to the cortical actin cytoskeleton and are thought to organize specialized membrane domains, perhaps through reciprocal relationships with members of the Rho family of small GTPases.

 

Inherited mutation of the human NF2 gene underlies the familial cancer syndrome Neurofibromatosis type 2, which features the development of nervous system tumors. Through genetic engineering in mice, we developed a mouse model of Nf2-associated tumorigenesis and a panel of tools for delineating the molecular basis of Merlin’s growth suppressing function. We found that Nf2 heterozygous mutant mice spontaneously develop a variety of metastatic tumors, including bone and liver tumors and that Nf2 function is required in multiple cell types during development. By studying primary Nf2-deficient mouse cells of several types, we have found that a key signature of Nf2-deficiency is the inability to undergo contact-dependent growth arrest via the formation of stable cadherin-containing cell:cell junctions. Our studies suggest that Merlin controls the stability of the mature adherens junction structure through its interaction with the actin cytoskeleton. Moreover, our studies indicate that Merlin coordinates the processes of adherens junction stabilization and negative regulation of certain membrane receptors such as the EGFR.

 

Current studies are aimed at further delineating this mechanism of Merlin function in adherens junction establishment and contact-dependent inhibition of proliferation.

Considerable evidence suggests that a functional relationship between Merlin and the closely related ERM proteins exists. Indeed, overexpression of Ezrin has been linked to tumor metastasis in several studies. We have recently generated a conditional Ezrin-mutant strain of mice and found that Ezrin is essential for organizing the apical surface of intestinal epithelial cells, providing fascinating insight into how epithelial cells polarize during tissue morphogenesis in vivo. These studies have also revealed new information about the three dimensional architecture and continuous turnover of the adult intestinal epithelium. Current studies aim to utilize these mice to study the functional relationship between Ezrin and Merlin in tissue morphogenesis and in tumor development and progression.

 

Our studies of Merlin function in the mouse suggest that Nf2-deficiency may play a surprisingly broad role in cancer development and progression. As we continue to define the molecular function of Merlin and the ERM proteins we hope to use this information to develop therapeutic strategies and test them in cell-based assays and preclinical mouse models of Nf2-associated tumor development.

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BBS webpage updated 12/02/2009