Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties

Jasmin Kaivola; Karolina Punovuori; Megan R. Chastney; Hind Abdo; Gautier Follain; Mathilde Mathieu; Omkar Joshi; Yekaterina A. Miroshnikova; Fabian Krautgasser; Jasmin Di Franco; James R.W. Conway; Sofia Held; Fabien Bertillot; Jaana Hagström; Antti Mäkitie; Heikki Irjala; Sami Ventelä; Hellyeh Hamidi; Giorgio Scita; Roberto Cerbino; Sara A. Wickström; Johanna Ivaska

doi:10.1038/s41563-025-02473-7

Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties

Jasmin Kaivola
, Karolina Punovuori
, Megan R. Chastney
, Hind Abdo
, Gautier Follain
, Mathilde Mathieu
, Omkar Joshi
, Yekaterina A. Miroshnikova
, Fabian Krautgasser
, Jasmin Di Franco
, James R.W. Conway
, Sofia Held
, Fabien Bertillot
, Jaana Hagström
, Antti Mäkitie
, Heikki Irjala
, Sami Ventelä
, Hellyeh Hamidi
, Giorgio Scita
, Roberto Cerbino

Sara A. Wickström, Johanna Ivaska (Corresponding author)

Computational and Soft Matter Physics

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

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.

Original language	English
Pages (from-to)	868–882
Number of pages	15
Journal	Nature Materials
Volume	25
Issue number	5
Early online date	20 Feb 2026
DOIs	https://doi.org/10.1038/s41563-025-02473-7
Publication status	Published - May 2026

Funding

We thank J. Siivonen, P. Laasola and C. Guzman for technical assistance and the Ivaska laboratory for scientific discussion. For services, instrumentation and expertise, we would like to thank the Cell Imaging and Cytometry Core (Turku Bioscience Centre, University of Turku) supported by Biocenter Finland, the Euro-BioImaging Finnish Node (Turku, Finland), the Finnish Functional Genomics Centre supported by the University of Turku, Åbo Akademi University and Biocenter Finland, and the Medical Bioinformatics Centre of Turku Bioscience Centre supported by the University of Turku, Åbo Akademi University, Biocenter Finland and Elixir-Finland, for the sequencing data analysis. Cytometry was performed at the Cell Imaging and Cytometry Core, Turku Bioscience Centre (Turku, Finland), with the support of Biocenter Finland. FIMM Digital Microscopy and Molecular Pathology Unit supported by HiLIFE and Biocenter Finland provided multiplex fluorescence immunohistochemistry and high-content imaging services. 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).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

103018 Materials physics
103015 Condensed matter
304009 Cell therapy

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Kaivola, J., Punovuori, K., Chastney, M. R., Abdo, H., Follain, G., Mathieu, M., Joshi, O., Miroshnikova, Y. A., Krautgasser, F., Di Franco, J., Conway, J. R. W., Held, S., Bertillot, F., Hagström, J., Mäkitie, A., Irjala, H., Ventelä, S., Hamidi, H., Scita, G., ... Ivaska, J. (2026). Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties. Nature Materials, 25(5), 868–882. https://doi.org/10.1038/s41563-025-02473-7

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title = "Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties",

abstract = "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.",

author = "Jasmin Kaivola and Karolina Punovuori and Chastney, \{Megan R.\} and Hind Abdo and Gautier Follain and Mathilde Mathieu and Omkar Joshi and Miroshnikova, \{Yekaterina A.\} and Fabian Krautgasser and \{Di Franco\}, Jasmin and Conway, \{James R.W.\} and Sofia Held and Fabien Bertillot and Jaana Hagstr{\"o}m and Antti M{\"a}kitie and Heikki Irjala and Sami Ventel{\"a} and Hellyeh Hamidi and Giorgio Scita and Roberto Cerbino and Wickstr{\"o}m, \{Sara A.\} and Johanna Ivaska",

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doi = "10.1038/s41563-025-02473-7",

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Kaivola, J, Punovuori, K, Chastney, MR, Abdo, H, Follain, G, Mathieu, M, Joshi, O, Miroshnikova, YA, Krautgasser, F, Di Franco, J, Conway, JRW, Held, S, Bertillot, F, Hagström, J, Mäkitie, A, Irjala, H, Ventelä, S, Hamidi, H, Scita, G, Cerbino, R, Wickström, SA & Ivaska, J 2026, 'Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties', Nature Materials, vol. 25, no. 5, pp. 868–882. https://doi.org/10.1038/s41563-025-02473-7

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AU - Kaivola, Jasmin

AU - Punovuori, Karolina

AU - Chastney, Megan R.

AU - Abdo, Hind

AU - Follain, Gautier

AU - Mathieu, Mathilde

AU - Joshi, Omkar

AU - Miroshnikova, Yekaterina A.

AU - Krautgasser, Fabian

AU - Di Franco, Jasmin

AU - Conway, James R.W.

AU - Held, Sofia

AU - Bertillot, Fabien

AU - Hagström, Jaana

AU - Mäkitie, Antti

AU - Irjala, Heikki

AU - Ventelä, Sami

AU - Hamidi, Hellyeh

AU - Scita, Giorgio

AU - Cerbino, Roberto

AU - Wickström, Sara A.

AU - Ivaska, Johanna

PY - 2026/5

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N2 - 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.

AB - 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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JF - Nature Materials

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Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

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