| 1. |
- Constantinou, Myrianni, et al.
(författare)
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Lineage specification in glioblastoma is regulated by METTL7B
- 2024
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Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 43:6
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastomas are the most common malignant brain tumors in adults; they are highly aggressive and heterogeneous and show a high degree of plasticity. Here, we show that methyltransferase-like 7B (METTL7B) is an essential regulator of lineage specification in glioblastoma, with an impact on both tumor size and invasiveness. Single-cell transcriptomic analysis of these tumors and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cell-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks.
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| 2. |
- Larsson, Ida, et al.
(författare)
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Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Nervous system cancers contain a large spectrum of transcriptional cell states, reflecting processes active during normal development, injury response and growth. However, we lack a good understanding of these states' regulation and pharmacological importance. Here, we describe the integrated reconstruction of such cellular regulatory programs and their therapeutic targets from extensive collections of single-cell RNA sequencing data (scRNA-seq) from both tumors and developing tissues. Our method, termed single-cell Regulatory-driven Clustering (scRegClust), predicts essential kinases and transcription factors in little computational time thanks to a new efficient optimization strategy. Using this method, we analyze scRNA-seq data from both adult and childhood brain cancers to identify transcription factors and kinases that regulate distinct tumor cell states. In adult glioblastoma, our model predicts that blocking the activity of PDGFRA, DDR1, ERBB3 or SOX6, or increasing YBX1-activity, would potentiate temozolomide treatment. We further perform an integrative study of scRNA-seq data from both cancer and the developing brain to uncover the regulation of emerging meta-modules. We find a meta-module regulated by the transcription factors SPI1 and IRF8 and link it to an immune-mediated mesenchymal-like state. Our algorithm is available as an easy-to-use R package and companion visualization tool that help uncover the regulatory programs underlying cell plasticity in cancer and other diseases.
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