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Gliomagenesis mimics an injury response orchestrated by neural crest-like cells

ABSTRACT: To explore the early steps in glioma formation, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging to initiate and then closely track tumour formation. We isolated labeled and unlabeled cells at multiple stages -- before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth -- and subjected each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogenous clonal hierarchy that evolves with tumour growth. By exploring the injury response in the wounded normal mouse brain, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response programme occurs during tumourigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of gliomagenesis, identifying a unique stem cell-like state and an injury response programme tied to early tumour formation. This will have implications on glioblastoma therapies and raises exciting new possibilities for early disease diagnosis and prevention. Some of the data in this series can also be explored through the following App link: gbm.stem-cells.ca.

ORGANISM(S): Mus musculus

PROVIDER: GSE278511 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:Owen1998 - tumour growth model Deterministic model for the early, avascular growth of a tumour, concentrating on the inhibitory effect of macrophages. This model is described in the article: Modelling the macrophage invasion of tumours: effects on growth and composition. Owen MR, Sherratt JA. IMA J Math Appl Med Biol 1998 Jun; 15(2): 165-185 Abstract: Even in the early stages of their development, tumours are not simply a homogeneous grouping of mutant cells; rather, they develop in tandem with normal tissue cells, and also recruit other cell types including lymphatic cells and the endothelial cells required for the development of a blood supply. It has been repeatedly seen that macrophages form a significant proportion of the tumour mass, and that they can have a variety of effects upon the tumour, leading to a delicate balance between growth promotion and inhibition. This paper develops a model for the early, avascular growth of a tumour, concentrating on the inhibitory effect of macrophages due to their cytolytic activity. It is shown that such an immune response is not sufficient to prevent growth, due to it being a second-order process with respect to the density of the tumour cells present. However, the presence of macrophages does have important effects on the tumour composition, and the authors perform a detailed bifurcation analysis of their model to clarify this. An extended model is also considered which incorporates addition of exogenous chemical regulators. In this case, the model admits the possibility of tumour regression, and the therapeutic implications of this are discussed. This model is hosted on BioModels Database and identified by: BIOMD0000000670. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Owen1998 - tumour treatment model This model is described in the article: Modelling the macrophage invasion of tumours: effects on growth and composition. Owen MR, Sherratt JA. IMA J Math Appl Med Biol 1998 Jun; 15(2): 165-185 Abstract: Even in the early stages of their development, tumours are not simply a homogeneous grouping of mutant cells; rather, they develop in tandem with normal tissue cells, and also recruit other cell types including lymphatic cells and the endothelial cells required for the development of a blood supply. It has been repeatedly seen that macrophages form a significant proportion of the tumour mass, and that they can have a variety of effects upon the tumour, leading to a delicate balance between growth promotion and inhibition. This paper develops a model for the early, avascular growth of a tumour, concentrating on the inhibitory effect of macrophages due to their cytolytic activity. It is shown that such an immune response is not sufficient to prevent growth, due to it being a second-order process with respect to the density of the tumour cells present. However, the presence of macrophages does have important effects on the tumour composition, and the authors perform a detailed bifurcation analysis of their model to clarify this. An extended model is also considered which incorporates addition of exogenous chemical regulators. In this case, the model admits the possibility of tumour regression, and the therapeutic implications of this are discussed. This model is hosted on BioModels Database and identified by: MODEL1708250002. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Gliomagenesis mimics an injury response orchestrated by neural crest-like cells

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