Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

Area of Science:

• Pediatric neuro-oncology
• Cancer epigenetics
• 3D cell culture models

Background:

• Atypical teratoid/rhabdoid tumors (ATRTs) are aggressive pediatric brain cancers.
• Genetic alterations in SWI/SNF chromatin remodelers (SMARCB1/SMARCA4) define ATRTs.
• Molecular subgroups of ATRTs exist, but subgroup-specific treatments are lacking due to inadequate preclinical models.

Purpose of the Study:

• To establish and characterize novel ATRT tumoroid models representing distinct molecular subgroups.
• To investigate the utility of these tumoroids for high-throughput drug screening.
• To identify potential subgroup-specific therapeutic vulnerabilities in ATRTs.

Main Methods:

• Establishment of ATRT tumoroids from ATRT-MYC and ATRT-SHH subgroups.
• Analysis of epigenetic and gene expression profiles to confirm subgroup fidelity.
• High-throughput drug screening to assess differential drug sensitivities.

Main Results:

• ATRT tumoroids successfully recapitulated subgroup-specific epigenetic and gene expression patterns.
• Significant differences in drug sensitivity were observed between and within ATRT-MYC and ATRT-SHH subgroups.
• ATRT-MYC models showed sensitivity to tyrosine kinase inhibitors, while ATRT-SHH models exhibited varied responses, including sensitivity to NOTCH inhibitors in a subset with high NOTCH receptor expression.

Conclusions:

• Developed the first pediatric brain tumor organoid models for ATRTs.
• Demonstrated the potential of ATRT tumoroids to reveal subgroup-specific drug responses.
• These models provide a platform for advancing the development of precision therapies for ATRTs.