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Elucidating Tumorigenesis Mechanisms and Assessing Immunotherapeutic Efficacy in Patient-Derived Medulloblastoma
Jiting Zhang1,2, Min Wang3, Huanwen Rui3
1State 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.
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.
Insights
Patient-derived medulloblastoma organoids (MBOs) accurately model tumor heterogeneity and microenvironment interactions. These MBOs show promise for testing novel therapies like tumor-infiltrating lymphocyte (TIL) immunotherapy against pediatric brain tumors.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Medulloblastoma is a common pediatric brain tumor with limited models for studying its complexity.
- Accurate models are crucial for understanding oncogenic mechanisms and therapeutic efficacy.
Purpose of the Study:
- To establish and characterize patient-derived medulloblastoma organoids (MBOs) as a novel research platform.
- To investigate the potential of MBOs for studying tumor microenvironment interactions and therapeutic responses.
- To explore novel therapeutic strategies, including immunotherapy, for medulloblastoma.
Main Methods:
- Generation of 10 patient-derived medulloblastoma organoids (MBOs).
- In vitro and in vivo assessment of MBO infiltration capabilities.
- Integrated omics profiling (RNA sequencing, whole-exome sequencing, DNA methylation).
- Single-cell transcriptomic analysis.
- Development of a prognostic nomogram.
- Evaluation of tumor-infiltrating lymphocytes (TILs) for immunotherapy.
Main Results:
- MBOs retained histological characteristics, cellular diversity, and molecular landscapes of parental tumors.
- MBOs demonstrated infiltration capabilities in vitro and in vivo, enabling tumor microenvironment studies.
- Photoreceptor-related pathways implicated in Group 4 medulloblastoma pathogenesis.
- A prognostic nomogram was developed using specific gene expression levels.
- Tumor-infiltrating lymphocytes showed significant cytotoxic activity against MBOs and suppressed tumor growth.
Conclusions:
- Patient-derived medulloblastoma organoids (MBOs) provide a faithful and versatile platform for medulloblastoma research.
- MBOs facilitate the investigation of tumor microenvironment interactions and accelerate therapeutic development.
- TIL-based immunotherapy shows significant potential for treating medulloblastoma.
