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Sonic hedgehog medulloblastoma cells in co-culture with cerebellar organoids converge towards in vivo malignant cell states

ABSTRACT: In the malignant brain tumour, sonic hedgehog medulloblastoma the properties of cancer cells are influenced by their microenvironment, but the nature of those effects and the phenotypic consequences for the tumour are poorly understood. The aim of this study was to identify phenotypic properties of SHH-MB cells that were driven by the non-malignant tumour microenvironment. Human iPSC were differentiated to cerebellar organoids to simulate the non-malignant tumour microenvironment. Tumour spheroids were generated from two distinct, long-established SHH-MB cell lines which were co-cultured with cerebellar organoids. We profiled the cellular transcriptomes of malignant and non-malignant cells by performing droplet-based single cell RNA-seq of thousands of cells. The transcriptional profiles of tumour cells in co-culture were compared with those of malignant cells cultured in isolation and with public SHH-MB datasets of patient tumours and PDX models. Heterogeneity of cell states was observed for SHH-MB cells cultured in isolation and in co-culture. Tumour cells in co-culture activated a key marker of differentiating granule cells, NEUROD1 that was not observed in control tumour cells cultured in isolation. In malignant cells in co-culture, cancer stem cell (CSC)-like states emerged that were not observed in control cultures and closely similar or equivalent cell states could be identified in patient tumours. For both SHH-MB cell lines grown in co-culture, there was a convergence of malignant cell states towards in vivo cell states observed in SHH-MB patient tumours and PDX models that were non-cell autonomously induced by the non-malignant microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254917 | GEO | 2024/04/01

REPOSITORIES: GEO

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Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adult. Based on transcriptome profile MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate Dehydrogenase-1 (IDH1) mutations have been described in several tumours, including gliomas, while in MB are exceptionally reported and not routinely investigated. By mean of magnetic resonance spectroscopy (MRS) we unequivocally assessed the presence the oncometabolite D-2-Hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutation, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also exceptionally described in MB. To our knowledge this is the first reported case of MB harboring both mutations together. Of note, tumour exhibited a heterogeneous phenotype with a tumour component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting coexistence of two different major tumour clones. These findings draw attention to the need of a deeper genetic characterization of MB in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, reported data underling the importance of performing MRS for the identification of IDH mutations in non-glial tumours. The use of throughput molecular profiling analysis and advanced medical imaging technology will certainly increase the frequency with which rare tumour entities will be identified. Whether they have any particular therapeutic implications or prognostic relevance requires further investigations.

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Sonic hedgehog medulloblastoma cells in co-culture with cerebellar organoids converge towards in vivo malignant cell states

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