ID #870 Immune-competent organoid fusion models to study extra cellular matrix dynamics in atypical teratoid rhabdoid tumour

Abstract

Atypical teratoid rhabdoid tumours (ATRTs) are highly aggressive paediatric brain tumours that primarily affect children under three years old, with limited effective treatment options resulting in a grim prognosis of 9 to 17.8 months. ATRT is characterised by loss-of-function mutations in the SMARCB1 gene, resulting in overreliance on SMARCA4, which drives chromatin remodelling and regulates a complex extracellular matrix (ECM). The ECM is now widely recognised as a key regulator of tumour progression and therapeutic resistance, however, its specific role in ATRT remains largely unexplored. In recent years, organoid technology, which enables the growth of miniature, simplified versions of human organs in the lab, has become a powerful platform for modelling human development and disease, particularly in neuro-oncology. However, ATRT-specific organoid models remain underdeveloped, and few systems incorporate the immune microenvironment.

In this study, we are developing a method for advanced organoid modelling to investigate the role of ECM in ATRT tumour immune microenvironment (TIME), with a novel emphasis on immune system interactions. We have generated cerebellum organoids from human induced pluripotent stem cells (hiPSCs) and integrate iPSC-derived microglial cells to develop immune-competent brain tissue models. These organoids are fused with patient-derived ATRT spheroids to recreate a tumour–host interface and enable analysis of tumour–ECM–immune interactions within a three-dimensional context.

This fused organoid model will allow high-resolution analysis of ECM protein expression, remodelling patterns, and spatial interactions with immune cells. By using membrane-proteomics, single-cell transcriptomics, imaging, and matrix invasion analyses, we will identify ECM-driven proteins that promote immune exclusion or suppression. Moreover, this platform provides an opportunity to uncover novel immunotherapy targets within the ECM landscape that could enhance immune infiltration and improve therapeutic response. Our research could lay the foundation for future immunotherapy strategies, offering new hope for children and their families impacted by this devastating disease.