Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties
: Kaivola, Jasmin; Punovuori, Karolina; Chastney, Megan R.; Abdo, Hind; Follain, Gautier; Mathieu, Mathilde; Joshi, Omkar; Miroshnikova, Yekaterina A.; Krautgasser, Fabian; Di Franco, Jasmin; Conway, James R. W.; Held, Sofia; Bertillot, Fabien; Hagström, Jaana; Mäkitie, Antti; Irjala, Heikki; Ventelä, Sami; Hamidi, Hellyeh; Scita, Giorgio; Cerbino, Roberto; Wickström, Sara A.; Ivaska, Johanna
Publisher: Springer Nature
: 2026
Nature Materials
: 1476-1122
: 1476-4660
DOI: https://doi.org/10.1038/s41563-025-02473-7
: https://doi.org/10.1038/s41563-025-02473-7
: https://research.utu.fi/converis/portal/detail/Publication/515716319
Increased extracellular matrix deposition and stiffness promotes solid tumour progression. Yet, the precise mechanotransduction pathways, especially in less-studied mechanically responsive cancers, remain poorly understood. Here we address this gap using patient-derived tumour cells from early (mobile, T1) and advanced (immobile, T3) stages of vocal fold cancer, the most common squamous cell carcinoma severely impacting the voice box. We reveal that vocal fold cancer progression is linked to cell surface receptor heterogeneity, a loss of laminin-binding integrins in cell–cell junctions and a flocking mode of collective cell motility. Mimicking the physiological movement of healthy vocal fold tissue with stretching or vibrations decreases oncogenic β-catenin and Yes-associated protein (YAP) nuclear levels in vocal fold cancer. Multiplex immunohistochemistry of vocal fold cancer tumours shows a correlation between the extracellular matrix composition, nuclear YAP and patient survival, concordant with vocal fold cancer sensitivity to oncogenic YAP-TEAD Hippo pathway inhibitors both in vitro and in vivo. Overall, our findings suggest that vocal fold cancer is a mechanically sensitive malignancy, and that the restoration of tumour mechanophenotype or YAP/TAZ targeting represents a tractable anti-oncogenic therapeutic avenue for vocal fold cancer.
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This study has been supported by the Molecular Regulatory Networks of Life (R’Life; 330033; to J.I. and S.A.W.), the Finnish Cancer Institute (K. Albin Johansson Professorship; to J.I.), a Research Council of Finland Centre of Excellence (grant numbers 346131 and 364182, to J.I.; grant numbers 346132 and 364186, to S.A.W.), the Cancer Foundation Finland (J.I.), the Sigrid Juselius Foundation (J.I.), the Research Council of Finland’s Flagship InFLAMES (grant numbers 337530 and 357910) and the Jane and Aatos Erkko Foundation (J.I.). This project was supported by an ERC grant (BorderControl; grant agreement number 101142305 to J.I.). J.K. was supported by the University of Turku Doctoral Program for Molecular Medicine and the Finnish Cultural Foundation. M.R.C. was supported by a Research Council of Finland postdoctoral research grant (grant number 343239). J.R.W.C. was supported by the European Union’s Horizon 2020 research and innovation programme under a Marie Skłodowska-Curie grant agreement (number 841973) and an Academy of Finland postdoctoral research grant (grant number 338585). H.A. is supported by a fellowship from Fondazione Umberto Veronesi. G.F. was supported by a Research Council of Finland postdoctoral research grant (grant number 332402) and a Turku Collegium for Science Medicine and Technologies postdoctoral fellowship. G.S. is supported by ERC-Synergy (grant number 101071470), AIRC-IG (grant number 22821), AIRC 5×1000 (grant number 22759) and the Italian Ministry of University and Research (PRIN202223GSCIT_01/G53D23002570006/20229RM8A_001, COMBINE/G53D23007040001/P2022RH4HH002 and PNRR_CN3RNA_SPOKE/G43C22001320007). Y.A.M. is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.
Open Access funding provided by University of Turku (including Turku University Central Hospital).
