Advillin protein stabilizes YAP to drive rhabdomyosarcoma growth

Rhabdomyosarcoma, the most common soft-tissue sarcoma in children, has long frustrated oncologists because metastatic and recurrent tumors respond poorly even to intensive multimodal therapy. Researchers led by Martyna Glowczyk-Gluc and colleagues, with senior author Hui Li, report that advillin, a gelsolin family actin-binding protein, sustains cancerous growth in rhabdomyosarcoma by stabilizing YAP, the key effector of the Hippo signaling pathway, and that tumors rich in advillin show heightened sensitivity to YAP inhibition.

The team had previously identified advillin, abbreviated AVIL, as an oncogenic driver overexpressed in rhabdomyosarcoma and linked to poor clinical outcomes. What remained unclear was how the protein actually exerted its tumor-promoting effects downstream. In the new work, the investigators examined AVIL expression in clinical rhabdomyosarcoma specimens spanning histologic subtypes, tumor grades and clinical stages, and found the protein broadly expressed across all of them.

Using transcriptomic, molecular and functional analyses in rhabdomyosarcoma cells, mesenchymal stem cells and patient-derived models, the researchers traced a direct line from AVIL to YAP. The study showed that AVIL promotes YAP stabilization and its nuclear accumulation, thereby enhancing YAP-dependent transcription alongside altered regulation of the Hippo pathway.

The functional consequences of removing AVIL were striking. Genetic depletion of AVIL impaired YAP signaling and rhabdomyosarcoma cell survival, and it pushed the cancer cells toward myogenic differentiation, a shift toward the muscle-forming identity the tumor had abandoned.

The study also probed how AVIL accomplishes this stabilization, and the answer appears to lie in actin remodeling. Advillin is an actin-binding protein, and when the researchers perturbed the actin cytoskeleton, the pool of nuclear YAP associated with AVIL diminished. Mutations that compromised AVIL’s actin-regulatory functions attenuated YAP activity and suppressed both proliferation and migration of the cancer cells.

The therapeutic implication emerges from a dependency experiment. Rhabdomyosarcoma models with high AVIL expression showed heightened sensitivity to YAP inhibition in vitro, whereas cells depleted of AVIL responded less to the same treatment.

To test whether that vulnerability holds up in living systems, the team turned to pharmacologic YAP inhibition in patient-derived xenograft models, transplanting patient tumor material into mice. Treatment suppressed YAP-dependent transcription and reduced tumor incidence in the AVIL-high xenografts.

The statistical framework behind the findings was correspondingly rigorous, spanning unpaired two-tailed t-tests, one-way ANOVA, log-rank survival analysis and REML-based mixed-effects models, with nonlinear regression used to determine IC50 values for the inhibitor studies. The work was published as an open access article on 04 November 2026 and is currently available as a peer-reviewed accepted manuscript, citable with a permanent DOI ahead of the final version of record.

The authors conclude that AVIL-mediated YAP dependency is a therapeutically actionable vulnerability and support targeting this pathway as a treatment strategy for aggressive rhabdomyosarcoma, a disease where novel molecularly targeted options remain an urgent unmet need.

Subject of Research: The role of the advillin–YAP signaling axis in sustaining oncogenic transcription and creating therapeutic vulnerability in rhabdomyosarcoma

Article Title: Advillin stabilizes YAP to sustain oncogenic transcription and creates therapeutic vulnerability in rhabdomyosarcoma

Article References: Glowczyk-Gluc, M., Zahra, S., Johnson, S., Xie, Z., Wang, Y., Ye, M., Fanburg-Smith, J., LeGallo, R. D., Alzayadneh, E., & Li, H. (2026). Advillin stabilizes YAP to sustain oncogenic transcription and creates therapeutic vulnerability in rhabdomyosarcoma. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03867-4

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03867-4

Keywords: rhabdomyosarcoma, advillin, YAP, Hippo pathway, oncogenic transcription, actin remodeling, pediatric sarcoma, YAP inhibition, patient-derived xenograft, myogenic differentiation, molecularly targeted therapy, cancer research