Elucidating Tumorigenesis Mechanisms and Assessing Immunotherapeutic Efficacy in Patient-Derived Medulloblastoma Organoid Models.

Overview

1. State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Greater Bay Area Institute of Precision Medicine (Guangzhou), Zhongshan Hospital, Fudan University, Shanghai, China
2. Human Phenome Institute, Fudan University, Shanghai, China
3. Department of Neurosurgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
4. Liangzhu Laboratory, Zhejiang University, Hangzhou, China
5. State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institute of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot, China
6. Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Cambridge-Suda Genomic Resource Center, Suzhou Medical College of Soochow University, Suzhou, China

Abstract

Medulloblastoma is one of the most common malignant pediatric brain tumors. There remain significant challenges in investigating oncogenic mechanisms and evaluating therapeutic efficacy due to the limited available models that accurately reflect tumor heterogeneity. To overcome this limitation, we established 10 patient-derived medulloblastoma organoids (MBOs) that retain the histological characteristics, and cellular diversity of the original tumors. These MBOs demonstrate strong infiltration capabilities, both in vitro through co-culture with human embryonic stem cell-derived cerebral organoids and in vivo following orthotopic or subcutaneous transplantation, establishing a potential platform for investigating interactions within the tumor microenvironment. Using integrated RNA sequencing, whole-exome sequencing, and DNA methylation profiling, we demonstrated that MBOs faithfully preserve the transcriptional, genomic, and epigenetic landscapes of their parental tumors. Single-cell transcriptomic analysis revealed conserved cellular subpopulation between MBOs and primary tumors. Our findings suggest that photoreceptor-related pathways may play an unprecedented role in the pathogenesis of Group 4 medulloblastoma and may be associated with interactions within the tumor microenvironment. Furthermore, we developed a prognostic nomogram based on IMPG2, BNC2, PAPPA2, ITGBL1and UNC13C expression levels in tumor cells to predict survival outcomes. Notably, tumor-infiltrating lymphocytes (TILs) expanded from patient specimens exhibited significant cytotoxic activity against autologous MBOs co-cultured in vitro and effectively suppressed the growth of subcutaneous MBO xenografts in vivo. These findings demonstrate the potential of TIL-based immunotherapy for medulloblastoma treatment. Collectively, our MBO system faithfully recapitulates critical tumor characteristics and serves as a valuable platform for investigating tumorigenic mechanisms and assessing therapeutic responses. This study not only promotes fundamental biological research but also accelerates clinical translation in medulloblastoma.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE85217 — at NCBI GEO; found in the text, “2.8 Differentially expressed genes analysis…”

Data availability

All raw sequencing data reported in this paper have been deposited in the Genome Sequence Archive (GSA). Specifically, the single-cell RNA sequencing (scRNA-seq) data are available under Project ID: PRJCA029327, PRJCA058601, and the transcriptomic, whole-exome, and DNA methylation sequencing data are available under Project ID: PRJCA052783.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 5 keywords, 11 MeSH terms, 59 references.

Cite

This paper

Zhang, J., Wang, M., Rui, H., Wang, C., Luo, G., Niu, Z., Shi, W., Zeng, J., Xue, P., Shi, X., Yan, B., Ren, W., Li, H., & Lin, X. (2026). Elucidating Tumorigenesis Mechanisms and Assessing Immunotherapeutic Efficacy in Patient-Derived Medulloblastoma Organoid Models. International journal of biological sciences, 22(9), 4878-4899. https://doi.org/10.7150/ijbs.116040

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