AVIL's dependency on YAP as a key mediator of oncogenic activity offers a therapeutic opportunity in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a prevalent pediatric soft-tissue cancer with a survival rate below 27% for high-risk patients. Despite significant genetic differences among RMS subtypes, frontline therapy remains largely uniform and ineffective for metastatic and recurrent cases. After decades of research, targeted therapies are currently unavailable, underscoring the urgent need for novel targets and effective treatment strategies. Our previous published studies identified AVIL as a novel, bona fide RMS oncogene. AVIL encodes a calcium-regulated, actin-binding protein critical for actin cytoskeleton organization. While its expression in healthy adult tissue is limited, AVIL is aberrantly upregulated in RMS and correlates with poor patient prognosis. AVIL silencing significantly reduces cell proliferation and migration, induces cell death in vitro , and prevents tumor formation in vivo . Our recent studies reveal that AVIL functions upstream of the transcriptional coactivator YAP, a key regulator of proliferation, survival, and stemness that is frequently hyperactivated in RMS. Through integrated transcriptomic, biochemical, and imaging analyses, we discovered that AVIL promotes YAP nuclear translocation, enhances its transcriptional activity, and increases cellular sensitivity to YAP pathway blockade. Conversely, genetic silencing of AVIL disrupts YAP signaling and restores the expression of myogenic differentiation markers, implicating AVIL's role in maintaining the undifferentiated, proliferative state of RMS cells. Functionally, AVIL-high RMS cells exhibit enhanced response to pharmacologic YAP inhibition, while AVIL depletion diminishes this effect, underscoring a mechanistic dependency of AVIL-driven oncogenic programs on YAP signaling. In vivo , administration of a YAP inhibitor to patient-derived RMS xenografts with high AVIL expression significantly reduces tumor incidence compared with vehicle-treated controls. Together, these findings uncover a previously unrecognized mechanism by which AVIL modulates YAP activity in RMS, revealing a therapeutically actionable axis that sustains tumor growth and impedes myogenic differentiation.