Matrix metalloproteinase 9: an emerging biomarker for classification of adherent vestibular schwannoma

Abstract

The progression of vestibular schwannoma (VS) is intricately linked with interactions between schwannoma cells and the extracellular matrix. Surgical resection of VS is associated with substantial risks as tumors are adherent to the brainstem and cranial nerves. We evaluate the role of matrix metalloproteinase 9 (MMP9) in VS and explore its potential as a biomarker to classify adherent VS. Transcriptomic analysis of a murine schwannoma allograft model and immunohistochemical analysis of 17 human VS were performed. MMP9 abundance was assessed in mouse and human schwannoma cell lines. Transwell studies were performed to evaluate the effect of MMP9 on schwannoma invasion in vitro. Plasma biomarkers were identified from a multiplexed proteomic analysis in 45 prospective VS patients and validated in primary culture. The therapeutic efficacy of MMP9 inhibition was evaluated in a mouse schwannoma model. MMP9 was the most highly upregulated protease in mouse schwannomas and was significantly enriched in adherent VS, particularly around tumor vasculature. High levels of MMP9 were found in plasma of patients with adherent VS. MMP9 outperformed clinical and radiographic variables to classify adherent VS with outstanding discriminatory ability. Human schwannoma cells secreted MMP9 in response to TNF-α which promoted cellular invasion and adhesion protein expression in vitro. Lastly, MMP9 inhibition decreased mouse schwannoma growth in vivo. We identify MMP9 as a pre-operative biomarker to classify adherent VS. MMP9 may represent a new therapeutic target in adherent VS associated with poor surgical outcomes that lack other viable treatment options.