Researchers at St. Jude Children’s Research Hospital and their collaborators have identified a distinct subset of neuroblastoma cells strongly associated with poor treatment responses in pediatric patients. The findings, detailed in Cancer Cell, address a longstanding obstacle in neuroblastoma research: the difficulty of separating malignant cells from healthy tissue within tumors. This breakthrough could refine how high-risk tumors are studied and treated.
Neuroblastoma is the most common solid tumor found outside of the brain in children, yet why some children respond well to treatment while others do not has remained poorly understood. While some children achieve remission with current therapies, others develop resistance and experience significantly lower survival rates. The study zeroes in on mesenchymal cells within tumors—cells that previous research had failed to reliably distinguish from their non-cancerous counterparts.
The team examined 54 tumor samples from 50 patients using single-cell RNA sequencing and spatial omics to map cellular differences. By generating patient-derived xenografts, where human tumor cells are grown in mice, they successfully isolated malignant mesenchymal cells while healthy mesenchymal cells from the same tumors did not proliferate in these models. This confirmed the genetic and behavioral divergence between cancerous and non-cancerous tissue.
A defining contribution was the development of a gene expression signature capable of consistently identifying these treatment-resistant mesenchymal cells. When compared against an external database of patient tumor RNA sequencing, the new signature surpassed older methods that relied on outdated cell lines from decades past. The improvement in accuracy could lead to better prognostic tools for neuroblastoma patients.
Further validation involved organoid cultures, additional cell lines, and expanded xenograft testing. The research confirmed that neuroblastoma tumors contain two primary cell types, adrenergic (associated with lower risk) and mesenchymal (linked to high risk), each exhibiting unique molecular and structural traits. These distinctions included variations in cell shape, internal organization, and functional behavior, all of which held true across different experimental approaches.
The researchers also established new cell lines and experimental models derived from patient samples containing varying ratios of mesenchymal and adrenergic cells. These resources, now accessible through St. Jude’s Childhood Solid Tumor Network, will enable other scientists to investigate high-risk neuroblastoma with greater precision. The objective is to uncover vulnerabilities in these aggressive tumors and assess potential therapeutic strategies.
The collaborative effort included scientists from the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, Stanford University, and other institutions. The study was supported by grants and contracts from the National Cancer Institute, the National Institutes of Health, the Howard Hughes Medical Institute, the Tully Family Foundation, the Peterson Foundation, Hyundai Hope on Wheels, the Damon Runyon Cancer Foundation, Alex’s Lemonade Stand Foundation, and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.