The continuous movement of the vocal cords weakens and eventually stops as laryngeal cancer progresses. An international team of researchers led by scientists at Turku Bioscience Centre, the University of Turku, and Åbo Akademi University has, for the first time, discovered that restoring cellular vibration reduces the aggressiveness of advanced vocal fold cancer (VFC), the most common type of squamous cell carcinoma that impacts the voice box.
Their study, involving work in cell culture models, analyses of human tissues, and tests in live mice, collectively showed that levels of a protein called Yes-associated protein (YAP), which promotes cancer growth and severity, decreased when cancer cells were exposed to sound-wave vibration. In vivo tests also revealed a previously unknown sensitivity of this cancer type to a targeted drug currently under development, pointing to YAP as a potential therapeutic target for VFC.
“We have a Research Council of Finland-funded Center of Excellence called Barrier Force where we have been exploring the mechanics of biological tissues for four years now,” said University of Turku research lead, professor Johanna Ivaska, PhD, director of the BarrierForce Centre of Excellence, speaking to GEN. “We hypothesized that for the vocal fold, the constant movement is important in maintenance of tissue homeostasis and that when this ceases, when cancer progresses, it would be feeding into the malignant behavior … Together with prof Sara Wickström’s team (members of our CoE), we joined forces to set up experiments with the vibration bioreactor. In addition, we have excellent clinical collaborators both at Turku and Helsinki University hospitals, who provided patient samples for the study.”
Ivaska is senior and co-corresponding author of the team’s published paper in Nature Materials, titled “Restoring the tumor mechanophenotype of vocal fold cancer reverts its malignant properties.”
The study included researchers from the BarrierForce Centre of Excellence and the InFLAMES Research Flagship. Conducted primarily in the research laboratory of Ivaska at the Turku Bioscience Centre in Finland, the work also involved three clinicians treating and studying oral cancers at the University Hospitals of Turku and Helsinki, as well as soft matter physicists from the University of Vienna and Milan.
What music should we play to our cells? This question sparked a groundbreaking study on laryngeal cancer. “Human vocal folds are composed of three layers (namely, epithelial, basement membrane, and lamina propria), with distinct cellular and extracellular matrix (ECM) compositions,” the authors explained. “Maintaining proper ECM organization is essential for vocal fold epithelium viscoelasticity, as it has been shown that the biomechanical and physiological performance of the vocal folds relies on ECM homeostasis.”
Changes to the ECM have been linked to different pathological conditions, including cancer. Laryngeal cancer is one of the most common malignant tumors of the head and neck region. The most significant risk factors are smoking and heavy alcohol consumption. The prognosis for advanced laryngeal cancer is poor, and there are currently no targeted drug therapies available.
Researchers have long known that increased tissue stiffness promotes cancer malignancy in non-moving tissues such as breast, liver, and pancreatic cancers, because cells sense and respond to the physical properties of their environment. “In recent years, there has been a growing appreciation of the role of ECM remodeling and increased deposition in cancer pathogenesis across a multitude of cancer types, as the ensuing increase in tissue rigidity alters tissue mechanics and drives disease progression,” the investigators stated. “However, it remains unknown whether changes in ECM and cell mechanics play a role in VFC. Further, it is not known whether immobility caused by fixation contributes to VFC malignancy or correlates with patient outcome.”
Ivaska explained to GEN, “We are working on integrins, which are cell adhesion receptors that regulate cell interactions with their environment. They are key sensors and regulators of mechanosensing by cells. In the past, we and others in the field have focused on mechanobiology in carcinomas arising in primarily non-motile tissue, such as the breast. However, we became curious to address how tissues that are constantly moving respond when they become immotile in growing tumors.”
![Microscopic images of two human laryngeal tumours, in which the cancer cells (green stain indicating YAP protein expression) are surrounded by stiffer connective tissue (red white violet). On the left is an early stage tumour, and on the right an advanced-stage tumour. [Karolina Punovuor/TURKU BIOSCIENCE CENTRE]](https://www.genengnews.com/wp-content/uploads/2026/03/mpIHC-images-for-press-release1-300x149.jpeg)
The most common early symptom of laryngeal cancer is hoarseness, as the cancer typically appears in the vocal cords, and their movement gradually becomes impaired as the disease develops. Movement decreases because the vocal cord tissue stiffens and the cancer invades surrounding tissue. “VFC progression causes vocal fold immobility as the squamous cell carcinoma invades the underlying muscle and tissues of the neck,” the authors noted. “VFC staging is based on the mobility status of the vocal folds and invasion into surrounding tissues … in T1–T2, the vocal folds move normally, whereas in T3–T4, mechanical fixation renders the vocal fold(s) immobile.”
The sensitivity of cells to external forces led researchers to take an interest in laryngeal cancer, which develops in constantly moving tissue. “We wondered whether ‘movement could be medicine’ and whether tissue stiffening and immobilization contribute to cancer development,” said Ivaska. “We developed this idea together with BarrierForce vice director and professor Sara Wickström, PhD, and her research group. “With their help, we used a bioreactor in which cells were grown on a vibrating membrane placed on top of a loudspeaker.”
In their report, the authors noted, “Given the established role of mechanical stress in tumor progression, we investigated how voice frequency mechanical strains impact tumorous vocal fold tissues, where transition from a freely vibrating to an immobilized state has been shown to correlate with poor prognosis.”
Lead author Jasmin Kaivola, PhD, who recently completed her doctoral degree at the University of Turku, came up with the idea of connecting an old mobile phone to the device to play sounds and music, and the experiments began. “PhD student Jasmin Kaivola was brave enough to take on the challenge to start looking into this unknown, as this is a bit of an out-of-the-box question in the field,” Ivaska told GEN.
The team’s predictions proved correct. They found that exposing cancer cells to vibration mimicking vocal cord movement reduced their malignancy. One of the observed changes was a decrease in the transcription factor protein YAP in the cells. YAP and another transcription factor, TAZ, are upregulated in different cancers and influence tumor initiation, progression, and resistance to treatment, the team noted. “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,” they reported. Ivaska further explained, “We observed that vibration downregulated the oncogenic protein nuclear YAP and nuclear β-catenin. In the in vivo models, we observed that inhibition of YAP-TEAD activity reduced tumor growth.”
Using samples of early-stage and advanced laryngeal cancer collected from approximately 200 Finnish patients, the researchers also found that elevated expression of proteins that increase tissue stiffness enhanced YAP activity and predicted mortality. “YAP-high tumors tended to have lower patient survival and higher staging,” the authors noted in their paper. Ivaska further commented to GEN, “The fact that our in vitro observed correlation of high nuclear YAP correlating with more malignant cells was valid and clinically relevant in vivo in a large patient cohort.”
In an experimental cancer model, the researchers discovered that the cancer was sensitive to a targeted drug under development that inhibits YAP protein activity. “We tested two, and one of these, I believe, is or at least has been in clinical trials for solid tumors,” Ivaska commented to GEN. “We wanted to test these as we noticed that restoring cell movement inhibited the activity of this pathway and that the most advanced T3 cancer cells were more sensitive to the drugs in vitro than the normal cells.”
The authors stated in their report, “… the YAP-TAZ-TEAD inhibitor treatment of mice with T3 tumors in the tongue (orthotopic transplantation) significantly limited tumor growth compared with control treatment.” The authors wrote in summary, “Multiplex immunohistochemistry of vocal fold cancer tumors 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.”
Kaivola noted that the study is groundbreaking because the biomechanics of developing cancers have not previously been studied in moving tissues. She added that it would be interesting to investigate whether the mechanism they identified has prognostic value in other cancers of moving tissues, such as lung cancer. “We are excited about the results and believe that our findings may encourage developers of these drugs to explore their suitability for this difficult-to-treat cancer with a poor prognosis.” The authors said, “These insights into the role of tissue mobility in maintaining homeostasis and suppression of malignancy may extend to other carcinomas arising from mobile epithelia and broaden our horizon on the mechanical control of cancer progression.”
Ivaska explained to GEN that the team aims to continue their research on additional HNSCC cancer cell lines and investigate in more detail the role of tissue movement to cancer invasion in this context. “We hope that our study would inspire companies working on the development of YAP-TEAD inhibitors to test their applicability in laryngeal cancer, as this cancer currently lacks effective targeted therapies.”
InFLAMES is a joint flagship initiative of the University of Turku and Åbo Akademi University. It aims to identify new drug development targets and promote drug development in collaboration with biotechnology and pharmaceutical companies. The flagship also advances diagnostics to enable tailored targeted therapies for patients. InFLAMES is part of the Academy of Finland’s Flagship Programme.
