Background Medulloblastoma (MB) is a heterogeneous disease in which neoplastic cells and associated immune cells contribute to disease progression. We aimed to determine the influence of neoplastic and immune cell diversity on MB biology in patient samples and animal models. Methods To better characterize cellular heterogeneity in MB we used single-cell RNA sequencing, immunohistochemistry and deconvolution of transcriptomic data to profile neoplastic and immune populations in patient samples and animal models across childhood MB subgroups. Results Neoplastic cells cluster primarily according to individual sample of origin which is influenced by chromosomal copy number variance. Harmony alignment reveals novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes, including photoreceptor and glutamatergic neuron-like cells in molecular subgroups GP3 and GP4, and a specific nodule-associated neuronally-differentiated subpopulation in subgroup molecular SHH. We definitively chart the spectrum of MB immune cell infiltrates, which include subpopulations that recapitulate developmentally-related neuron-pruning and antigen presenting myeloid cells. MB cellular diversity matching human samples is mirrored in subgroup-specific mouse models of MB. Conclusions These findings provide a clearer understanding of the diverse neoplastic and immune cell subpopulations that constitute the MB microenvironment.
Medulloblastoma (MB) is a heterogeneous disease in which neoplastic cells and associated immune cells contribute to disease progression. To better understand cellular heterogeneity in MB we profile neoplastic and immune populations in childhood MB samples using single-cell RNA sequencing, immunohistochemistry and deconvolution of transcriptomic data. Neoplastic cells cluster primarily according to individual sample of origin which is in part due to the effect of chromosomal copy number gains and losses. Harmony alignment reveals novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes and are associated with clinical outcomes. We identify discrete photoreceptor-like cells in MB subgroups GP3 and GP4 and nodule-associated neuronally-differentiated cells in subgroup SHH. MB immune infiltrates consist of both developmentally-related neuron-pruning and antigen presenting myeloid cells. We show that this MB cellular diversity is recapitulated in genetically engineered mouse subgroup-specific models of MB. These findings advance our understanding of both the neoplastic and immune landscape of MB.
Posterior reversible encephalopathy syndrome was described in 1996 as a clinical-neuroimaging entity characterized by parieto-occipital watershed-region edema without overt infarction. It has been linked to hypertension, eclampsia, immunosuppressive therapies, infections, and autoimmune disorders. The condition usually has an acute onset, presents with seizures, and ameliorates within days. There have been few neuropathological studies, but in some cases, tissue damage may be more permanent.
Several subtypes of adult GBM (MG-PNET, posterior fossa GBMs, E-GBMs) have recently been recognized to have a propensity for LM; autopsy permission should especially be sought for these tumor types. Correlation between genetics and LM/SVS is now possible and may shed further light on this behavior.
Background The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant. Methods Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data. Results PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA. Conclusions These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression.
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