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In vivo intratumoral Heterogeneity in a dish: Scalable Forebrain Organoid Models of Embryonal Brain Tumors for High-Throughput Personalized Drug Discovery (human organoids subset 2)

ABSTRACT: Embryonal brain tumors (EBTs), arising during early brain development, present significant challenges in understanding pathogenesis and developing treatments. This study explores the efficacy of forebrain organoid models in replicating the complexities of the EBT microenvironment. We established an EBT-forebrain-organoid (EBT-FBO) model, incorporating embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid and rhabdoid tumor (ATRT), using a scalable liquid-handling-assisted coaggregation method. Comprehensive characterization, including wholemount immunostaining, immunohistochemistry, single-cell RNA sequencing, integration with existing datasets, and automated cell-type-specific drug screening, validated the EBT-FBO model. EBT-FBOs closely mimicked mid-gestational fetal brain environments, with EBTs reflecting intratumoral heterogeneity at both histological and transcriptomic levels. Drug screening on ETMR-FBOs identified promising treatment options, including anthracyclins and Triptolide, which demonstrated anti-tumoral effects with minimal neurotoxicity. Scalable EBT-FBO models that resemble immature neuronal microenvironments similar to ETMR or ATRT mark significant progress towards targeted therapy and personalized precision medicine that requires recapitulation of individual tumor heterogeneities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270066 | GEO | 2025/11/13

REPOSITORIES: GEO

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In vivo intratumoral Heterogeneity in a dish: Scalable Forebrain Organoid Models of Embryonal Brain Tumors for High-Throughput Personalized Drug Discovery (human+murine organoids subset)

Project description:Embryonal brain tumors (EBTs), arising during early brain development, present significant challenges in understanding pathogenesis and developing treatments. This study explores the efficacy of forebrain organoid models in replicating the complexities of the EBT microenvironment. We established an EBT-forebrain-organoid (EBT-FBO) model, incorporating embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid and rhabdoid tumor (ATRT), using a scalable liquid-handling-assisted coaggregation method. Comprehensive characterization, including wholemount immunostaining, immunohistochemistry, single-cell RNA sequencing, integration with existing datasets, and automated cell-type-specific drug screening, validated the EBT-FBO model. EBT-FBOs closely mimicked mid-gestational fetal brain environments, with EBTs reflecting intratumoral heterogeneity at both histological and transcriptomic levels. Drug screening on ETMR-FBOs identified promising treatment options, including anthracyclins and Triptolide, which demonstrated anti-tumoral effects with minimal neurotoxicity. Scalable EBT-FBO models that resemble immature neuronal microenvironments similar to ETMR or ATRT mark significant progress towards targeted therapy and personalized precision medicine that requires recapitulation of individual tumor heterogeneities.

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Project description:Embryonal brain tumors (EBTs), arising during early brain development, present significant challenges in understanding pathogenesis and developing of treatments. This study explores the efficacy of forebrain organoid (FBO) models in replicating the complexities of the EBT microenvironment. We established an EBT-forebrain-organoid (TBO) model, incorporating embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid and rhabdoid tumor (ATRT), using a scalable liquid-handling-assisted coaggregation method. Comprehensive characterization, including wholemount immunostaining, immunohisto-chemistry, single-cell RNA sequencing, integration with existing datasets, and automated cell type-specific drug screening, validated the TBO model. TBOs closely mimicked mid-gestational fetal brain environments, and EBTs in FBOs better approximated native intratumoral heterogeneity at both histological and transcriptomic levels than tumor-only 3D approaches. Drug screening in ETMR-FBOs identified promising treatment options, including anthracyclins and triptolide, demonstrating anti-tumoral effects with minimal neurotoxicity. Scalable TBO models that incorporate immature neural microenvironments better recapitulate individual tumor heterogeneity and mark significant progress towards targeted therapy and personalized precision medicine.

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