Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage

• Published in: Nature communications Vol. 15; no. 1; pp. 269 - 20
• Main Authors: Ghasemi, David R., Okonechnikov, Konstantin, Rademacher, Anne, Tirier, Stephan, Maass, Kendra K., Schumacher, Hanna, Joshi, Piyush, Gold, Maxwell P., Sundheimer, Julia, Statz, Britta, Rifaioglu, Ahmet S., Bauer, Katharina, Schumacher, Sabrina, Bortolomeazzi, Michele, Giangaspero, Felice, Ernst, Kati J., Clifford, Steven C., Saez-Rodriguez, Julio, Jones, David T. W., Kawauchi, Daisuke, Fraenkel, Ernest, Mallm, Jan-Philipp, Rippe, Karsten, Korshunov, Andrey, Pfister, Stefan M., Pajtler, Kristian W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/32; 38/39; 38/91; 45; 45/90; 631/136/142; 692/4028/67/1922; 692/4028/67/2329; 692/4028/67/2332; 692/420/755; Brain cancer; Cell Differentiation; Cerebellar Neoplasms - genetics; Cerebellum; Compartments; Datasets; Disease Progression; DNA methylation; Genotype & phenotype; Histological Techniques; Histology; Humanities and Social Sciences; Humans; Immune system; Medulloblastoma; Medulloblastoma - genetics; multidisciplinary; Phenotypes; Precursors; Science; Science (multidisciplinary); Spatial analysis; Transcriptomes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44117-x

Medulloblastomas with extensive nodularity are cerebellar tumors characterized by two distinct compartments and variable disease progression. The mechanisms governing the balance between proliferation and differentiation in MBEN remain poorly understood. Here, we employ a multi-modal single cell transcriptome analysis to dissect this process. In the internodular compartment, we identify proliferating cerebellar granular neuronal precursor-like malignant cells, along with stromal, vascular, and immune cells. In contrast, the nodular compartment comprises postmitotic, neuronally differentiated malignant cells. Both compartments are connected through an intermediate cell stage resembling actively migrating CGNPs. Notably, we also discover astrocytic-like malignant cells, found in proximity to migrating and differentiated cells at the transition zone between the two compartments. Our study sheds light on the spatial tissue organization and its link to the developmental trajectory, resulting in a more benign tumor phenotype. This integrative approach holds promise to explore intercompartmental interactions in other cancers with varying histology. The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.