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Phenotypic mapping of pathological crosstalk between glioblastoma and innate immune cells by synthetic genetic tracing

Item Type:Article
Title:Phenotypic mapping of pathological crosstalk between glioblastoma and innate immune cells by synthetic genetic tracing
Creators Name:Schmitt, M.J. and Company, C. and Dramaretska, Y. and Barozzi, I. and Göhrig, A. and Kertalli, S. and Großmann, M. and Naumann, H. and Sanchez-Bailon, M.P. and Hulsman, D. and Glass, R. and Squatrito, M. and Serresi, M. and Gargiulo, G.
Abstract:Glioblastoma is a lethal brain tumor which exhibits heterogeneity and resistance to therapy. Our understanding of tumor homeostasis is limited by a lack of genetic tools to selectively identify tumor states and fate transitions. Here, we use glioblastoma subtype signatures to construct synthetic genetic tracing cassettes and investigate tumor heterogeneity at cellular and molecular level, in vitro and in vivo. Through synthetic locus control regions, we demonstrated that proneural glioblastoma is a hardwired identity, whereas the mesenchymal glioblastoma is an adaptive and metastable cell state driven by pro-inflammatory and differentiation cues and DNA damage, but not hypoxia. Importantly, we discovered that innate immune cells divert glioblastoma cells to a proneural-to-mesenchymal transition which confers therapeutic resistance. Our synthetic genetic tracing methodology is simple, scalable and widely applicable to study homeostasis in development and diseases. In glioblastoma, the method causally links distinct (micro)environmental, genetic and pharmacological perturbations and mesenchymal commitment.
Keywords:Glioblastoma Heterogeneity, Innate Immunity, Molecular Subtypes, Genetic Tracing, Synthetic Biology, Systems Biology, Therapeutic Resistance, Genetic Screens, Inflammation, Animals, Mice
Source:Cancer Discovery
ISSN:2159-8274
Publisher:American Association for Cancer Research
Date:23 December 2020
Official Publication:https://doi.org/10.1158/2159-8290.CD-20-0219
PubMed:View item in PubMed

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