May 9, 2003

Researchers identify important function of NF2 tumor suppressor

An MGH-based research team has identified a key cellular function of a protein involved in the rare genetic disorder neurofibromatosis type 2 (NF2), characterized by multiple tumors of the spine and brain. The NF2 gene was discovered in 1993 by researchers from MGH and elsewhere. At that time it was apparent that the NF2 gene was a tumor suppressor, but its exact function was unclear. The protein encoded by the NF2 gene, given the name merlin, was found at the interface of the cell membrane with the cytoskeleton, a network of filaments that supports the cell.

The researchers, led by Andrea McClatchey, PhD, of the MGH Cancer Center, found that cells from mice lacking a normal NF2 gene did not stop multiplying when they came into contact with other cells. Normal cells stopped growing when they filled the culture dish, but the NF2-deficient cells kept piling up on each other, suggesting they could not sense touching other cells. The NF2-deficient cells also lacked key cellular structures called adherens junctions, which play a role in cell-to-cell communications. Adding normal merlin protein to cultures of NF2-deficient cells restored both the formation of adherens junctions and contact-dependent growth inhibition. The report is in the May 1, 2003, issue of Genes & Development.

"Our study suggests that merlin normally organizes the structure that facilitates cell-to-cell communication," says McClatchey. "Loss of junction integrity has been linked to both tumor development and tumor invasion, providing an explanation for the striking development of metastatic cancer in NF2-mutant mice."

In humans, NF2 mutations also have been associated with mesothelioma, a highly malignant type of lung cancer caused by asbestos exposure, and possibly with other forms of cancer. The current finding also supports a growing theory that, for some tumors, the capacity to metastasize is inherent from the original tumor-inducing mutation rather than being acquired as a tumor keeps developing. McClatchey's co-authors include first author Dominique Lallemand, PhD; Marcello Curto, MD, PhD; and Ichiko Saotome of the MGH Cancer Center.