Single-cell RNA sequencing reveals ECM remodeling-tumor stiffness-FAK as a key driver of vestibular schwannoma progression

Vestibular schwannoma (VS), characterized by the absence of merlin expression, is the most prevalent benign tumor located at the cerebellopontine angle, lacking approved pharmaceutical interventions except for off-label utilization of bevacizumab. The role of Tumor stiffness-Focal adhesion kinase (FAK) activation in fueling tumor progression is well-established, with merlin deficiency serving as a biomarker for tumor sensitivity to FAK inhibitors. In this context, we investigated whether Tumor stiffness-FAK contributes to VS progression. Single-cell RNA sequencing revealed associations between VS progression and gene sets related to “Response to mechanical stimulus” and “Neurotrophin signaling pathway”. Histological studies indicated a potential involvement of neurotrophins in early stages of VS tumorigenesis, while enhanced Extracellular matrix (ECM) remodeling-Tumor stiffness-FAK signaling accompanies later stages of VS progression. In vitro experiments demonstrated that elevated matrix stiffness induces cytoskeletal remodeling, cell proliferation, and metalloproteinase expression in VS cells by activating FAK. Conversely, FAK inhibition diminishes these effects. Collectively, this study suggests that ECM remodeling-Tumor stiffness contributes to VS progression via FAK activation, positioning FAK as a promising therapeutic target in treating VS.