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Updated: Sep 10, 2025
Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts
Published on: June 13, 2019
Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition
Femke C A S Ringnalda1,2, Gijs J F van Son1,2, Laurens H G Verweij1,2
1Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Abstract:
Small round cell sarcomas (SRCS) are highly aggressive tumors in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeutic regimen. Although several pre-clinical models of Ewing sarcoma have been established, such as cell lines and patient-derived tumor xenografts, few models exist for other SRCS. Here, we describe a pediatric SRCS tumor organoid (tumoroid) biobank containing long-term tumoroid cultures with different translocations, including EWSR1::FLI1, EWSR1::ERG, CIC::DUX4, and BCOR-rearrangements. Using histology, whole genome sequencing and RNA sequencing, we demonstrate that these tumoroids retain histological characteristics, known marker gene expression and chromosomal rearangements of their matching patient tumors. In addition, we compare mutation clusters in the tumoroids across patient-matched longitudinal samples, which shows that cellular heterogeneity is maintained. Drug screening on the tumoroid models unveils entity-specific drug sensitivity to various cytotoxic compounds and targeted compounds, including MCL-1 inhibitors for CIC::DUX4 sarcomas. Taken together, this newly established SRCS patient-derived tumoroid biobank represents a promising source of material for future basic cancer research and drug screening.
Insights
A new biobank of pediatric small round cell sarcoma (SRCS) tumoroids preserves tumor characteristics and reveals entity-specific drug sensitivities, offering a promising resource for cancer research and drug discovery.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Small round cell sarcomas (SRCS) are aggressive pediatric tumors with limited preclinical models for non-Ewing sarcoma subtypes.
- Current therapeutic regimens for SRCS are standardized despite diverse underlying genetics and pathology.
- Existing models like cell lines and xenografts are insufficient for studying the heterogeneity of various SRCS.
Purpose of the Study:
- To establish and characterize a biobank of pediatric small round cell sarcoma (SRCS) patient-derived tumoroids.
- To assess the fidelity of tumoroid models in recapitulating patient tumor characteristics, including genetics and heterogeneity.
- To utilize tumoroid models for drug screening and identify potential targeted therapies for specific SRCS entities.
Main Methods:
- Development of long-term tumoroid cultures from pediatric SRCS patient samples with diverse translocations.
- Histological analysis, whole genome sequencing, and RNA sequencing to validate tumoroid fidelity.
- Comparison of tumoroid mutation clusters with longitudinal patient samples to assess cellular heterogeneity.
- Drug screening using cytotoxic and targeted compounds on established tumoroid models.
Main Results:
- The tumoroid biobank successfully maintains histological features, gene expression markers, and chromosomal rearrangements of patient tumors.
- Tumoroids accurately reflect the cellular heterogeneity observed in longitudinal patient samples.
- Drug screening identified entity-specific sensitivities, including MCL-1 inhibitors for CIC::DUX4 sarcomas.
Conclusions:
- The established SRCS tumoroid biobank is a valuable resource for preclinical research.
- Tumoroids provide a faithful platform for studying SRCS biology and heterogeneity.
- This resource enables effective drug screening, paving the way for personalized therapeutic strategies in SRCS.
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