Abstract
NF2-related schwannomatosis (NF2-SWN) is a devastating tumor predisposition syndrome marked by multiple schwannomas and substantial morbidity. Vestibular Schwannoma (VS), the hallmark tumor, causes deafness, vertigo and potentially fatal brainstem compression. A subset develops brainstem adhesions, making surgery - the only treatment option - highly risky in the absence of FDA-approved therapies. During NF2-SWN progression, schwannoma cells migrate from the extracellular matrix (ECM)-rich internal auditory canal to the arachnoid-lined brainstem, yet mechanisms driving this transition remain incompletely defined. We previously demonstrated that adherent schwannoma is associated with elevated matrix metalloproteinase-9 (MMP-9) activity. N-cadherin (N-cad), a key cell-matrix adhesion molecule and regulator of cancer cell migration, has not been studied in NF2-SWN. Integrating RNA sequencing, multiple NF2 schwannoma mouse models and primary human VS cultures, we demonstrate that N-cad is overexpressed in sporadic and NF2-associated VS. N-cad differentially regulates VS spheroid migration - promoting motility on astrocytes but restraining on ECM. MMP-9 cleaves N-cad to drive schwannoma proliferation through IL-6/STAT3 and NF-κB signaling. Pharmacologic and genetic inhibition of N-cad synergized with dasatinib and brigatinib, two kinase inhibitors with efficacy in NF2-SWN, to suppress schwannoma proliferation and tumor growth. These findings establish N-cad as a central regulator of schwannoma migration and a novel therapeutic target.