Gap Junction-Mediated Communication in Schwannoma Development
Abstract
Schwannomas that form around the acoustic and other cranial and spinal nerves are the hallmark of neurofibromatosis type 2 (NF2) and related familial schwannomatosis. Both familial NF2 and sporadic schwannomas are caused by mutation of the NF2 tumor suppressor gene, with few cooperating mutations. Despite this genetic uniformity, tumor behavior and therapeutic response is remarkably heterogeneous. Currently, surgical resection is the primary treatment option and patients are often subject to multiple, high-risk surgeries as tumors inevitably recur. As such, targeted pharmacological therapies for schwannomas are desperately needed, but few have been developed and most of those that have reached clinical trials have shown heterogeneous responses and limited efficacy. Our recent studies of schwannoma development in a mouse model have revealed that the earliest lesions form adjacent to neuronal cell bodies in the ganglia of the peripheral nervous system and express markers of a type of Schwann cells that normally form a single-layered coat around these cell bodies. Our preliminary data showed that these lesions progressively express Cx43, a protein that forms gap junctions, a type of intercellular connection that enables the direct passage of small molecules between the cytoplasm of two cells. Gap junction mediated communication plays an important role in chronic pain in the peripheral nervous system and drives tumor growth and drug resistance in other types of tumors, particularly in the central nervous system. However, no one has investigated the role of gap junctions in schwannomas. The overarching goal is to test the hypothesis that cells in schwannomas are coupled by and functionally depend on gap junctions. We will test this hypothesis using cells and tissues from a well-established mouse model of schwannoma, and from human schwannomas, along with state-of-the-art imaging techniques. The successful completion of these studies may uncover a completely new understanding of schwannoma biology and multiple new avenues of therapeutic possibility. The research proposed here has the potential to benefit schwannoma patients, especially those with NF2 or schwannomatosis, who are in desperate need of new therapeutic options. In particular, gap junction-mediated communication has been linked to chronic pain, an important non-tumor manifestation of schwannoma that could be targeted with gap junction blockers. Substantial focus on developing targeted therapies for schwannoma based on studies of cells grown in 2D in non-physiological conditions has yielded disappointing results. We believe that focusing on the complex biology of schwannoma is a better approach and will reveal new therapeutic ideas. Gap junction proteins could represent important biomarkers for schwannomas or could be targeted using gap junction blockers, which are widely used in preclinical studies and are currently being tested in clinical trials. While the studies proposed here only scratch the surface of a potential role for gap junctions in schwannoma and more comprehensive studies to unravel the complex biological structure of gap junctions will be required, it is important to note that the gap junction blocker currently being clinically evaluated, MFA, is an FDA-approved drug that is licensed as a non-steroidal anti-inflammatory drug, potentially shortening the time to testing in patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310541
Entities
People
- Christine Mackenzie
Organizations
- Massachusetts General Hospital
- United States Army