| Autor: |
Sutcliffe, Matthew D., Galvao, Rui P., Wang, Lixin, Kim, Jungeun, Singh, Shambhavi, Zong, Hui, Janes, Kevin A. |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| DOI: |
10.1101/2020.03.30.017228 |
| Popis: |
Cancer evolves from premalignant clones that accumulate mutations and adopt unusual cell states to achieve transformation. Tracking a cancer cell-of-origin through the cell-state alterations of premalignancy could provide clues for early-detection and cancer-prevention strategies. Previously we pinpointed the oligodendrocyte precursor cell (OPC) as a cell-of-origin for glioma. However, the early adaptations and cell-state changes of mutant OPCs during premalignancy are unknown. Using a genetically engineered mouse model (GEMM) of inducible Nf1–Trp53 loss in OPCs, we acutely isolated labeled mutant OPCs by laser-capture microdissection and determined gene-expression changes in two ways: global changes in gene expression were measured by differential analysis of wild-type and mutant OPCs after bulk RNA sequencing; cell-to-cell state variations were identified by a fluctuation analysis, called stochastic profiling, which uses RNA-sequencing measurements from random pools of 10 mutant cells. We chose two time points for the analysis. At 12 days after Nf1–Trp53 deletion, while bulk differences were mostly limited to increases in mitotic hallmarks and decreases in ribosome biosynthesis, stochastic profiling of mutant OPCs revealed a spectrum of stem-progenitor, proneural, and mesenchymal states as potential starting points for gliomagenesis. At 90 days after Nf1–Trp53 deletion, while bulk sequencing detected very few differentially expressed transcripts, stochastic profiling revealed multiple cell states that are absent from glial tumors, suggesting that they marked dead-ends for gliomagenesis. In parallel, we identified cells without dead-end markers but abundantly expressing key effectors of nonsense-mediated decay and homology-dependent DNA repair. This suggests that resolution of replication stress may pose a considerable bottleneck for glioma initiation in premalignant mutant OPCs. Statement of significance In situ heterogeneity profiling of cell states in a mouse model of glioma uncovers regulatory confusion in a glioma cell-of-origin and defines a state of replication stress that precedes tumor initiation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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