Data_Sheet_2_MMP-14 (MT1-MMP) Is a Biomarker of Surgical Outcome and a Potential Mediator of Hearing Loss in Patients With Vestibular Schwannomas.DOCX

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（vestibular schwannoma, VS）是桥小脑角最常见的肿瘤，现有临床生物标志物预测价值欠佳，因此亟需开发针对性的新型生物标志物。肿瘤大小、生长速率等临床指标无法阐明伴随感音神经性听力损失（sensorineural hearing loss, SNHL）的病理生理机制，且特异性与敏感性较低；而组织学标志物仅能取样部分肿瘤组织，且难以在肿瘤治疗或外科干预前完成检测。蛋白酶在肿瘤发生发展中发挥多样且关键的调控作用，有望成为前庭神经鞘瘤的新型生物标志物类别。本研究结合生物信息学分析（in silico）、体外（in vitro）及离体（ex vivo）实验手段，通过对人类前庭神经鞘瘤转录组开展目前规模最大的荟萃分析，从一组差异表达的候选蛋白酶中筛选鉴定出基质金属蛋白酶14（matrixmetalloprotease 14, MMP-14；又称MT1-MMP）。前庭神经鞘瘤患者血浆及肿瘤分泌液中MMP-14的表达丰度与蛋白水解活性，与临床参数及感音神经性听力损失程度呈显著相关。此外，患者血浆MMP-14水平与手术切除范围等外科预后指标密切相关。最后，将生理浓度的MMP-14应用于耳蜗外植体培养体系后，可造成螺旋神经节神经元纤维及突触损伤，从而为阐明前庭神经鞘瘤相关性感音神经性听力损失的发病机制提供了直接的实验依据。综上，MMP-14是一种新型分子生物标志物，有望在前庭神经鞘瘤的诊断与预后评估中得到进一步验证与应用。