Role of Merlin/NF2 in mTOR Signaling and Meningioma Growth

Principal Investigator: RAMESH, VIJAYA
Program: NFRP
Proposal Number: NF100047
Award Number: W81XWH-11-1-0264
Funding Mechanism: Investigator-Initiated Research Award - Optional Collaborator
Partnering Awards:
Award Amount: $1,181,731.00


Neurofibromatosis 2, abbreviated as NF2, is a genetic disease caused by alterations in the NF2 gene, which results in loss of function of the NF2 protein known as merlin. NF2 patients primarily develop tumors pathologically classified as schwannomas and meningiomas. When complete loss of merlin occurs in either Schwann cells, which wrap around nerve cells, or meningeal cells, which line the area between the brain and the inside of the skull, the result is the formation of schwannoma or meningioma tumors, respectively. After the NF2 gene was identified in 1993, many laboratories focused their work on understanding the functions of the NF2 protein merlin. Numerous functions of merlin in various cell types have been described; however, how merlin's absence results specifically in schwannomas and meningiomas in NF2 remains unknown. A major problem in the NF2 research field is the lack of human tumor-derived cell lines, along with their normal counterparts required to perform necessary biological experiments. For example, until recently, meningioma cell lines were limited, and meningeal cells (also known as arachnoidal cells), their normal counterpart from which meningiomas arise, could not be easily obtained.

Due to the efforts of scientists and physicians at Massachusetts General Hospital, as well as the willingness of patients and relatives to participate in research studies, we have established critical tumor cell lines along with normal cell lines. Using these cells, we have recently discovered a new role for merlin, which explains the growth of the tumors in NF2. Our results for the first time show that the NF2 protein merlin regulates an important signaling pathway known as mTOR. We have observed abnormal increase in mTOR signaling in meningiomas and schwannomas when merlin is lost. One of the aims proposed in this project seeks to define exactly how merlin regulates mTOR signaling. The other aims are devoted to testing agents that are known to block the abnormal activation of mTOR signaling, in cell culture and mouse meningioma models. It is of interest to note that mTOR signaling is activated in other disorders such as neurofibromatosis 1 (NF1) and tuberous sclerosis complex (TSC), where patients develop slow growing benign tumors, similar to NF2. Agents that block mTOR activation are currently being tested in clinical trials of NF1 and TSC. Our work therefore will provide similar avenues for treating NF2 patients.