Molecular changes during AT/RT progression associated with epithelial-mesenchymal transition and extracellular matrix...

Area of Science:

• Pediatric neuro-oncology
• Cancer genomics
• Tumor microenvironment research

Background:

• Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive infant brain tumors with poor outcomes.
• Tumor progression and recurrence are common in AT/RT, but the mechanisms driving these are poorly understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying tumor relapse and therapy resistance in AT/RT.
• To identify potential therapeutic targets for improving AT/RT treatment outcomes.

Main Methods:

• Single-nucleus RNA sequencing (snRNAseq) of paired primary and recurrent AT/RT tumors.
• Analysis of tumor cells and tumor microenvironment (TME) components.
• CIBERSORT for identifying therapy-resistant cells.
• Validation through histopathology, in vitro experiments, bulk RNA sequencing, and survival analysis.

Main Results:

• Significant global gene expression differences were observed between primary and recurrent AT/RT.
• Therapy-resistant AT/RT-MYC cells exhibited altered extracellular matrix (ECM) components, developmental processes, and immune signaling.
• Gene signatures associated with resistance correlated with inferior survival in AT/RT-MYC patients.
• Relapsed AT/RT-MYC cells demonstrated partial epithelial-mesenchymal transition (pEMT), confirmed by immunohistochemistry (IHC) and in vitro studies.

Conclusions:

• This study identifies potential mechanisms driving AT/RT relapse and therapy resistance.
• Altered ECM, developmental pathways, immune signaling, and pEMT are implicated in AT/RT recurrence.
• Findings provide a basis for developing novel therapeutic strategies to overcome AT/RT resistance.