A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours

Abstract

Human cerebral cancers are known to contain cell types resembling the varying stages of neural development. However, the basis of this association remains unclear. Here, we map the development of mouse cerebrum across the developmental time-course, from embryonic day 12.5 to postnatal day 365, performing single-cell transcriptomics on >100,000 cells. By comparing this reference atlas to single-cell data from >100 glial tumours of the adult and paediatric human cerebrum, we find that tumour cells have an expression signature that overlaps with temporally restricted, embryonic radial glial precursors (RGPs) and their immediate sublineages. Further, we demonstrate that prenatal transformation of RGPs in a genetic mouse model gives rise to adult cerebral tumours that show an embryonic/juvenile RGP identity. Together, these findings implicate the acquisition of embryonic-like states in the genesis of adult glioma, providing insight into the origins of human glioma, and identifying specific developmental cell types for therapeutic targeting.

Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers

“…We used scRegClust to integrate the regulatory programs from the developing brain (Couturier et al , 2020; Eze et al , 2021; Hamed et al , 2022; Luo et al , 2021; La Manno et al , 2021; Weng et al , 2019), normal adrenal gland (Kildisiute et al , 2021), GBM (Couturier et al , 2020; Darmanis et al , 2017; LeBlanc et al , 2022; Neftel et al , 2019; Wang et al , 2019), MB (Hovestadt et al , 2019; Luo et al , 2021; Ocasio et al , 2019) and neuroblastoma (NB) (Kildisiute et al , 2021). We ran the algorithm for each data set individually and merged the resulting regulatory tables (Figure 4A, Figure S2, Supplementary Table 2).…”

The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials

“…As a first step, to explore the plausible correlation of genomic factors that overlap between aging and schizophrenia (Figure 1A), relevant scRNA-seq datasets were re-analysed to identify the specific neural lineage, stage in differentiation, and developmental periods that show the extent to which schizophrenia risk genes are detected. Utilising an scRNAseq atlas resource of over 100,000 cells across various lineages from the mouse forebrain, spanning from embryonic day 12.5 (E12.5) through to one year of life [64], we applied Seurat v5 for standard analysis procedures [65]. The 'AddModuleScore' function was used to calculate a 'geneset' score for each cell within the scRNA-seq dataset, based on the activities of schizophrenia risk genes.…”

“…Upon verification of the increased expression of schizophrenia-associated genes in OL lineage cells, we further explored additional scRNA-seq datasets from different studies. These datasets were selected since they were generated from the same 10x v3 platform to investigate periventricular forebrain cells across a time span ranging from postnatal day 0 through to 2 years of age [64,[66][67][68][69]. Initially, all datasets from various published studies were merged, and integration was carried out using the Single Cell Variational Inference (scVI) package in the python programming language in python [70].…”

Learning cell identity in immunology, neuroscience, and cancer

“…Broadly speaking, it is difficult to determine whether a CSC is a cancer cell that has shifted its identity into a stem-like cell as a mechanism for more favorable survival, or rather a cell that arises from a population of healthy stem cells that have transformed into a malignant state [ 28 ]. When evaluating the existence of CSCs, it is important to keep in mind their potential for differentiation or plasticity, including the reemergence of states that resemble cells normally seen in earlier development [ 114 ]. Subsets of cells with different phenotypes are observed within and between tumors from different patients, and only some of these cell subsets will behave as CSCs in functional assays [ 17 , 115 – 117 ].…”