Despite decades of progress in pediatric oncology, outcomes for children with high-risk or recurrent rhabdomyosarcoma (RMS) remain discouragingly low. While some patients with intermediate-risk disease experience long-term remission, survival for those with relapsed or refractory tumors can dip below 20%. Researchers at Fred Hutch and the University of Washington are working to understand why these tumors return—and what molecular changes accompany their evolution after treatment.
RMS, the most common soft tissue sarcoma in children, is a highly heterogeneous disease. Risk and treatment outcomes depend on several factors, including tumor site, patient age, and a key genetic feature: whether the tumor carries a PAX3/7::FOXO1 fusion gene. These fusions divide RMS into two major subtypes—fusion-positive (FP-RMS) and fusion-negative (FN-RMS)—with distinct biology and clinical behavior. Patients with FN-RMS generally fare better, whereas FP-RMS tumors, especially those with PAX3::FOXO1 fusions, are often resistant to therapy and more likely to recur.
Current treatment approaches for RMS rely heavily on radiation for local control alongside systemic chemotherapy. Yet even with high-dose, precisely targeted irradiation, many patients relapse. Larger or more aggressive tumors tend to resist therapy, highlighting the urgent need for biomarkers that can predict recurrence or point to new treatment strategies.
Recently published in Pediatric Blood & Cancer, a new study from Dr. Omar Mian’s lab contains transcriptomic analyses of tumor samples collected at both diagnosis and relapse to explore how RMS evolves over the course of therapy. By comparing the bulk tumor gene expression profiles from these paired samples, the investigators sought to identify molecular and pathway-level changes that could explain how some RMS tumors survive initial therapy and adapt to treatment pressure.
“We demonstrate that treatment failure is accompanied by subtype-specific shifts in myogenic differentiation and inflammatory signaling,” shared Mian. “Notably, the enrichment of the myogenesis pathway and differentiation markers in fusion-negative tumors after treatment represents a novel observation that may inform future therapeutic strategies.”
These findings reveal that rhabdomyosarcomas evolve differently under therapy depending on their fusion status, with fusion-negative tumors showing unique vulnerabilities to differentiation-based treatments such as MEK inhibition—a targeted therapy that blocks the MEK protein kinase to slow or stop the growth of cancer cells by disrupting the RAS/MAPK signaling pathway. This observation raises the possibility that FN-RMS tumors may respond to drugs that push them toward a more differentiated, less aggressive state.
The study also prompts new questions about the tumor microenvironment’s role in shaping these responses. Macrophages, immune cells that can either attack or support tumor growth, were found to be linked with inflammatory signaling patterns at relapse. These cells can secrete cytokines that promote inflammation, remodel surrounding tissue, and influence how tumor cells mature or resist therapy. Understanding whether macrophage-driven inflammation actively promotes relapse—or reflects an immune system struggling to contain the disease—could reveal new therapeutic entry points.
Looking ahead, Mian and his team plan to extend this work via spatial transcriptomics, which provides gene expression information while maintaining the context of tissue architecture, to better map the cellular interactions that drive RMS progression. “Our research will integrate transcriptomic and spatial profiling to dissect these immune–myogenic interactions and test whether differentiation-directed therapies can reprogram resistant tumor cells in a fusion-specific manner,” he explained.
By illuminating how RMS evolves under therapeutic pressure, this research lays the groundwork for more personalized approaches to treating relapsed disease—approaches that consider not only the tumor’s genetic drivers but also the cellular ecosystem that sustains it.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Omar Mian contributed to this research.
The spotlighted research was funded by the National Institutes of Health and the VeloSano Foundation Research Grant.
Muskara A, Parthasarathy PB, Oyarbide U, Ma Y, Ganguly S, Imamura J, Liao R, Rubin BP, Macaskill A, Murphy ES, Anderson PM, Gryder BE, Scott JG, Zahler SG, Mian OY. 2025. Transcriptomic Profiling of Relapsed Rhabdomyosarcoma: Pre- and Post-Treatment Tissue Analysis Reveals Molecular Characteristics of Treatment Failure. Pediatric Blood & Cancer. DOI: 10.1002/pbc.31864.
Science Spotlight writer Jenny Waters is a postdoctoral research fellow in the Hsieh lab at Fred Hutch. She studies how mRNA translation coordinates bladder cancer transformation and metastasis by post-transcriptionally regulating expression of oncogenic proteins. Outside of the lab, Jenny enjoys spending time with her dogs, convincing her husband to join her on trail runs, and pretending every steep hill is just a "gentle incline."
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