Abstract 7048: Molecular and immune landscape of extracranial malignant rhabdoid tumors (eMRT) and atypical teratoid rhabdoid tumors (ATRT): Insights into disease mechanisms
Authors: Maria D. Hernandez Ramirez, Marlena Mucha, Victoria E. Fincke, Martin Hasselblatt, Christian Vokuhl, Michael C. Frühwald, Pascal D. Johann
Journal: Cancer Research (2025)

Abstract Rhabdoid tumors are aggressive pediatric cancers characterized by significant alterations in gene expression and tumor microenvironment composition. Our study aims to investigate the molecular mechanisms driving tumor aggressiveness and relapse in extracranial malignant rhabdoid tumors (eMRT) and atypical teratoid rhabdoid tumors (ATRT). Using high-resolution single-cell RNA sequencing and spatial transcriptomics, we analyzed gene expression patterns and cellular interactions within the tumor microenvironment, with a particular focus on immune cell composition and activity. Previous research has identified distinct DNA methylation subgroups in eMRT, associated with clinical outcomes such as high- and standard-risk profiles. These subgroups, linked to differences in survival rates, relapse frequencies, and SMARCB1 genetic alterations, provide a foundational framework for understanding tumor heterogeneity. Building on this framework, we explored subgroup-specific gene expression profiles and tumor microenvironmental dynamics, moving beyond methylation-based stratification. Pathway enrichment analysis identified key molecular pathways associated with immune evasion and tumor progression, providing insights into the tumor microenvironment and its role in disease progression. We observed enrichment in pathways such as nuclear-transcribed mRNA catabolic process (nonsense-mediated decay), and cytoplasmic translation, which are crucial for sustaining the high proliferative rates of tumor cells. Unique to the high-risk group in eMRT is the enrichment of pathways such as protein phosphorylation and plasma membrane-bounded cell projection assembly, which are critical for oncogenic signaling and invasive mechanisms. Immune cell characterization revealed a higher macrophage count in the eMRT high-risk group compared to the standard-risk group, aligning with their aggressive phenotype, as macrophages facilitate invasion and immune evasion. The high-risk eMRT group also showed elevated levels of growth factors (FGF9, HGF, PDGFC) and invasion-related proteins (SEMA3D, IL1RAPL1), with reduced ALB levels, which suggest enhanced proliferation and metabolic alterations characteristic of aggressive tumors. These findings offer a deeper understanding of the unique molecular and cellular landscapes of rhabdoid tumors, providing valuable insights to inform potential therapeutic targets. Citation Format: Maria D. Hernandez Ramirez, Marlena Mucha, Victoria E. Fincke, Martin Hasselblatt, Christian Vokuhl, Michael C. Frühwald, Pascal D. Johann. Molecular and immune landscape of extracranial malignant rhabdoid tumors (eMRT) and atypical teratoid rhabdoid tumors (ATRT): Insights into disease mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7048.