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Phenotypic mapping of pathologic cross-talk between glioblastoma and innate immune cells by synthetic genetic tracing

Item Type:Article
Title:Phenotypic mapping of pathologic cross-talk 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 Sánchez-Bailón, M.P. and Hulsman, D. and Glass, R. and Squatrito, M. and Serresi, M. and Gargiulo, G.
Abstract:Glioblastoma is a lethal brain tumor that 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 levels, in vitro and in vivo. Through synthetic locus control regions, we demonstrate that proneural glioblastoma is a hardwired identity, whereas mesenchymal glioblastoma is an adaptive and metastable cell state driven by proinflammatory 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 that 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 pharmacologic perturbations and mesenchymal commitment. SIGNIFICANCE: Glioblastoma is heterogeneous and incurable. Here, we designed synthetic reporters to reflect the transcriptional output of tumor cell states and signaling pathways' activity. This method is generally applicable to study homeostasis in normal tissues and diseases. In glioblastoma, synthetic genetic tracing causally connects cellular and molecular heterogeneity to therapeutic responses.
Keywords:Glioblastoma Heterogeneity, Innate Immunity, Molecular Subtypes, Genetic Tracing, Synthetic Biology, Systems Biology, Therapeutic Resistance, Genetic Screens, Inflammation
Source:Cancer Discovery
Publisher:American Association for Cancer Research
Page Range:754-777
Date:March 2021
Additional Information:copyright ©2020 American Association for Cancer Research
Official Publication:https://doi.org/10.1158/2159-8290.CD-20-0219
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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