Neuron-Glial Interactions in Schwannoma Initiation and Heterogeneity
Abstract
Schwannomas that form around the auditory and other cranial and spinal nerves are the hallmark of Neurofibromatosis type 2 (NF2) and related schwannomatoses. It is a mystery as to why they form around some nerves and not others when Schwann cells and their relatives surround all nerves of the peripheral nervous system. Moreover, mutation of the NF2 tumor suppressor gene underlies most if not all familial and sporadic schwannomas with few if any additional mutations, yet these tumors behave, look and respond to drugs in very different and inconsistent ways. Surgery is currently the primary treatment option and patients are often subject to multiple, high-risk surgeries as tumors inevitably recur. The few targeted therapies that have been developed have shown heterogeneous and limited efficacy. New ideas for developing therapies for schwannoma are desperately needed. Studies of other types of malignant brain tumors have revealed that chemical signaling between neurons and the glial cells that they interact with is very important for tumor development and expansion. Our lab has recently begun to develop an atlas of schwannoma development in well-established and validated mouse models and human tumor tissue. These studies have taught us about how schwannomas initiate and develop and suggest that they form around specific neuronal subtypes, supporting the notion that chemical signals from nerves trigger schwannoma initiation and subsequent heterogeneous development. The studies proposed here will begin to test this completely new idea. Given the wealth of existing information about neuronal signaling and vast resources dedicated to building a pipeline of drugs that modify neuronal signals, these studies could rapidly open up completely new therapeutic opportunities for schwannoma patients. They could also help to explain and combat the chronic pain that is associated with many schwannomas. In the longer term, these studies can be expanded to include studies of other forms of familial schwannomatosis using available mouse models (Smarcb1-, Lztr- mutant) and human tissue.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310380
Entities
People
- Andrea I McClatchey
Organizations
- Massachusetts General Hospital
- United States Army