Improved biomarkers are needed for vestibular schwannoma (VS), the most common tumor of the cerebellopontine angle, as existing clinical biomarkers have poor predictive value. Factors such as tumor size or growth rate do not shed light on the pathophysiology of associated sensorineural hearing loss (SNHL) and suffer from low specificity and sensitivity, whereas histological markers only sample a fraction of the tumor and are difficult to ascertain before tumor treatment or surgical intervention. Proteases play diverse and critical roles in tumorigenesis and could be leveraged as a new class of VS biomarkers. Using a combination of in silico, in vitro, and ex vivo approaches, we identified matrixmetalloprotease 14 (MMP-14; also known as MT1-MMP), from a panel of candidate proteases that were differentially expressed through the largest meta-analysis of human VS transcriptomes. The abundance and proteolytic activity of MMP-14 in the plasma and tumor secretions from VS patients correlated with clinical parameters and the degree of SNHL. Further, MMP-14 plasma levels correlated with surgical outcomes such as the extent of resection. Finally, the application of MMP-14 at physiologic concentrations to cochlear explant cultures led to damage to spiral ganglion neuronal fibers and synapses, thereby providing mechanistic insight into VS-associated SNHL. Taken together, MMP-14 represents a novel molecular biomarker that merits further validation in both diagnostic and prognostic applications for VS.

前庭神经鞘瘤 (VS) 是小脑桥脑角最常见的肿瘤，需要改进的生物标志物，因为现有的临床生物标志物的预测价值很差。肿瘤大小或生长速度等因素无法揭示相关感音神经性听力损失 (SNHL) 的病理生理学，并且特异性和敏感性较低，而组织学标记仅对肿瘤的一小部分进行取样，并且在肿瘤治疗或治疗前难以确定手术治疗。蛋白酶在肿瘤发生中发挥着多种多样的关键作用，可以作为一类新的 VS 生物标志物加以利用。使用的组合在计算机中,体外， 和离体方法，我们从一组候选蛋白酶中鉴定出基质金属蛋白酶 14（MMP-14；也称为 MT1-MMP），这些蛋白酶通过对人类 VS 转录组的最大荟萃分析进行差异表达。VS 患者血浆和肿瘤分泌物中 MMP-14 的丰度和蛋白水解活性与临床参数和 SNHL 程度相关。此外，MMP-14 血浆水平与手术结果相关，例如切除范围。最后，将生理浓度的 MMP-14 应用于耳蜗外植体培养物会导致螺旋神经节神经元纤维和突触受损，从而提供对 VS 相关 SNHL 的机制洞察。总之，MMP-14 代表了一种新型分子生物标志物，值得在 VS 的诊断和预后应用中进一步验证。