Kaivola Jasmin, Punovuori Karolina, Chastney Megan R, Miroshnikova Yekaterina A, Abdo Hind, Bertillot Fabien, Krautgasser Fabian, Franco Jasmin Di, Conway James R W, Follain Gautier, Hagström Jaana, Mäkitie Antti, Irjala Heikki, Ventelä Sami, Hamidi Hellyeh, Scita Giorgio, Cerbino Roberto, Wickström Sara A, Ivaska Johanna
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki Finland.
bioRxiv. 2024 Aug 23:2024.08.22.609159. doi: 10.1101/2024.08.22.609159.
Increased extracellular matrix (ECM) and matrix stiffness promote solid tumor progression. However, mechanotransduction in cancers arising in mechanically active tissues remains underexplored. Here, we report upregulation of multiple ECM components accompanied by tissue stiffening in vocal fold cancer (VFC). We compare non-cancerous (NC) and patient-derived VFC cells - from early (mobile, T1) to advanced-stage (immobile, T3) cancers - revealing an association between VFC progression and cell-surface receptor heterogeneity, reduced laminin-binding integrin cell-cell junction localization and a flocking mode of collective cell motility. Mimicking physiological movement of healthy vocal fold tissue (stretching/vibration), decreases oncogenic nuclear β-catenin and YAP levels in VFC. Multiplex immunohistochemistry of VFC tumors uncovered a correlation between ECM content, nuclear YAP and patient survival, concordant with VFC sensitivity to YAP-TEAD inhibitors in vitro. Our findings present evidence that VFC is a mechanically sensitive malignancy and restoration of tumor mechanophenotype or YAP/TAZ targeting, represents a tractable anti-oncogenic therapeutic avenue for VFC.
细胞外基质（ECM）增加和基质硬度升高会促进实体瘤进展。然而，机械活跃组织中发生的癌症的机械转导仍未得到充分研究。在此，我们报告了声带癌（VFC）中多种ECM成分上调并伴有组织硬化。我们比较了非癌（NC）和患者来源的VFC细胞——从早期（可移动，T1期）到晚期（不可移动，T3期）癌症——揭示了VFC进展与细胞表面受体异质性、层粘连蛋白结合整合素细胞间连接定位减少以及集体细胞运动的聚集模式之间的关联。模拟健康声带组织的生理运动（拉伸/振动），可降低VFC中致癌性核β-连环蛋白和YAP水平。VFC肿瘤的多重免疫组织化学揭示了ECM含量、核YAP与患者生存率之间的相关性，这与VFC在体外对YAP-TEAD抑制剂的敏感性一致。我们的研究结果表明，VFC是一种机械敏感的恶性肿瘤，恢复肿瘤机械表型或靶向YAP/TAZ，是VFC一种可行的抗癌治疗途径。
