Researchers have uncovered new clues about why the childhood cancer rhabdomyosarcoma may become aggressive.
Some children diagnosed with rhabdomyosarcoma (RMS) appear to have lower-risk disease, yet their cancer can still become dangerously aggressive. Researchers have now uncovered biological similarities that may explain why, raising the possibility of identifying these children earlier and matching treatment more closely to their actual risk.
Published in Cancer Research, the study brought together researchers from the Wellcome Sanger Institute, the University of Cambridge, Great Ormond Street Hospital (GOSH), University College London, and collaborating institutions. They investigated the genetic forces behind RMS, an aggressive cancer that develops from muscle tissue. RMS is among the most common soft tissue cancers in children younger than 15, with about 55 cases diagnosed in the UK each year.
Childhood cancers differ from many cancers that develop in adults. Rather than being strongly associated with aging or environmental exposures, they commonly arise from developmental changes that increase the likelihood of cancer forming.
RMS is generally divided into two major groups based on whether a tumor carries a particular genetic risk marker. That marker forms when two genes that are normally separate become fused together. Children whose tumors contain this fusion have substantially poorer survival than those without it, even with intensive treatment.
But the usual classification does not explain every case. Some children whose tumors lack this high-risk marker nevertheless develop aggressive disease, leaving researchers with the question of what drives those cancers.
Single cells exposed hidden aggressive disease
Researchers at the Wellcome Sanger Institute, the University of Cambridge, and their collaborators set out to investigate what distinguishes these aggressive cancers in patients who had initially been categorized as non-high-risk.
They compared tumors from children with high-risk and non-high-risk RMS using genomic techniques that allowed them to examine cancer cells in much greater detail. One method, single-cell RNA sequencing, measures gene activity separately in individual cells rather than averaging signals across an entire tumor. That approach exposed aggressive cancer cells hidden within tumors that conventional classification had labeled non-high-risk.
The researchers also used spatial transcriptomics, a technique that preserves information about where cells are positioned inside tissue while measuring their gene activity. This allowed them to see how aggressive cell populations were arranged throughout the tumors.
The results showed that aggressive tumors from children classified as non-high-risk had patterns of gene activity closely resembling those found in high-risk tumors, even though they did not carry the established genetic risk marker.
The researchers also identified rare genetic alterations in aggressive non-high-risk tumors that disrupted the same cellular pathways affected in high-risk disease. This indicates that different genetic changes can ultimately lead cancer cells toward a similar aggressive state.
Different mutations converge on aggressive disease
Finding distinctive markers on these high-risk cells could eventually help researchers develop more targeted treatments. Possible approaches include immunotherapies such as CAR-T cell therapy, which could potentially attack cancer cells more selectively while limiting some of the side effects associated with conventional chemotherapy.
The researchers also hope the findings could eventually improve how children are classified at diagnosis. More accurate identification of aggressive tumors could allow clinicians to intensify treatment for patients most likely to relapse while sparing genuinely lower-risk patients from unnecessary treatment toxicity.
To build on the findings, the researchers are expanding their analysis to hundreds of additional tumor samples. Their goal is to uncover more of the rare genetic routes that can produce aggressive childhood cancer and support the development of more precise treatments for young patients.
Findings could refine treatment decisions
Dr Karin Straathof, co-senior author at UCL Cancer Institute and GOSH, said: “By studying tumors one cell at a time, we uncovered hidden populations of aggressive cancer cells that conventional methods miss. Although these tumors carry different genetic changes, many converge on the same aggressive pathways. This helps explain why some children who appear to have lower risk disease can still have a devastating outcome.”
Sara Wakeling, Chief Executive Officer and co-founder of Alice’s Arc, said: “Every child with cancer deserves the best possible chance of survival. We’re proud to support research into rhabdomyosarcoma showing how cutting-edge technologies can uncover the biology driving aggressive childhood cancers. These discoveries bring us closer to more personalized treatments and better outcomes for children.”
Dr Laura Danielson, Children’s and Young Person’s Lead at Cancer Research UK, said: “Discovery research like this is essential to understand the unique biology of these cancers. This important study demonstrates that aggressive tumors may share similar features, even if they carry different genetic changes. By helping researchers understand what these high-risk cancers have in common, this work adds a vital piece to the puzzle and could help guide future efforts to improve treatment for children and young people with rhabdomyosarcoma.”
Professor Sam Behjati, co-senior author formerly at the Wellcome Sanger Institute and Head of the Department of Pediatrics at the University of Cambridge, said: “This work changes how we think about rhabdomyosarcoma. Rather than a single, abnormal gene, we’ve shown that there is an overarching cell state of aggressive disease that defies conventional classification systems. Understanding this shared biology could help identify children who need more intense treatment to improve their survival.”
Reference: “High-Risk Rhabdomyosarcomas Feature a Convergent Cell State” by Holly J. Whitfield, Nathaniel D. Anderson, Christina Burke, Marian J. Groot Koerkamp, Conor Parks, Toochi Ogbonnah, Yvette Wood, Alice Piapi, Emilia Robertson, Eleanor Watt, Abigail White, Solange De Noon, Jonathan Kennedy, Rajvi Nagrecha, Michael T. Meister, Ewa Aladowicz, Yang Kee Stella Man, Virginia Laspidea, Mi K. Trinh, Angus Hodder, Tarryn Porter, John E. Lawrence, Elizabeth Tuck, Trung Nguyen, Anna Kelsey, Adrienne M. Flanagan, Richard Hewitt, Naima Smeulders, Olga Slater, J. Ciaran Hutchinson, Neil Sebire, Janet M. Shipley, Jarno Drost, Karin Straathof and Sam Behjati, 19 August 2026, Cancer Research.
DOI: 10.1158/0008-5472.CAN-25-4403
This research was supported by a Cancer Research UK – Children with Cancer UK Innovation Award and co-funded by Alice’s Arc. Additional funding was provided by Wellcome.
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