Project description:To comprehensively define the cellular heterogeneity of glioblastoma (GBM), the GBM CARE (Cellular Analysis of Resistance and Evolution) consortium set out to profile 121 GBMs with extensive clinical annotation, by single-nucleus RNA-sequencing and bulk tumor DNA sequencing. The resulting dataset enabled us to characterize GBM heterogeneity at three levels. First, GBMs are classified by their cellular composition, encompassing malignant, immune, neuronal and glial cell types. Second, within each cell type, and particularly among the malignant cells, we describe the diversity of cellular states and their pathway-based functional activities. Third, after controlling for the frequencies of cellular states, we find that the remaining variation between GBMs highlights three baseline gene expression programs which we labeled Neuronal, Glial, and Extracellular Matrix. These three layers of heterogeneity are inter-related and partially associated with specific genetic aberrations, thereby defining three stereotypic ecosystems in GBM. This work provides an unparalleled view of the multi-layered transcriptional architecture of GBM.
Project description:To comprehensively define the cellular heterogeneity of glioblastoma (GBM), the GBM CARE (Cellular Analysis of Resistance and Evolution) consortium set out to profile 121 GBMs with extensive clinical annotation, by single-nucleus RNA-sequencing and bulk tumor DNA sequencing. The resulting dataset enabled us to characterize GBM heterogeneity at three levels. First, GBMs are classified by their cellular composition, encompassing malignant, immune, neuronal and glial cell types. Second, within each cell type, and particularly among the malignant cells, we describe the diversity of cellular states and their pathway-based functional activities. Third, after controlling for the frequencies of cellular states, we find that the remaining variation between GBMs highlights three baseline gene expression programs which we labeled Neuronal, Glial, and Extracellular Matrix. These three layers of heterogeneity are inter-related and partially associated with specific genetic aberrations, thereby defining three stereotypic ecosystems in GBM. This work provides an unparalleled view of the multi-layered transcriptional architecture of GBM.
Project description:Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics with novel computational approaches to uncover the organization of glioma cellular states. We find three prominent modes of organization. First, cells in any given state tend to be spatially clustered, with local environments that are each enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. Third, the pairwise interactions that we detect collectively define a global architecture composed of five layers. Hypoxia appears to drive this 5-layered organization, as it is associated with a long-range organization that extends from the hypoxic core to the infiltrative edge of the tumor. Accordingly, tumor regions distant from any hypoxic foci are less organized. In summary, we provide a conceptual framework for the organization of gliomas and highlight the role of hypoxia as a potential long-range tissue organizer.
Project description:The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Through computational analyses of large-scale tissue transcriptomes, we unveiled that the chaperone system is composed of core elements that are uniformly expressed across tissues, and variable elements that are differentially expressed to fit with tissue-specific requirements. We demonstrate via a proteomic analysis of a mouse myoblast cell line that the muscle-specific signature is functional and conserved. Core chaperones were significantly more abundant across tissues and more important for cell survival than variable chaperones. Together with variable chaperones, they formed tissue-specific functional networks. Analysis of human organ development and aging brain transcriptomes revealed that these functional networks were maintained in development and declined with age. Our findings expand the known functional organization of de novo versus stress-inducible eukaryotic chaperones into a layered core-variable architecture in multi-cellular organisms.