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Published on: January 12, 2020
Notch activation is associated with tetraploidy and enhanced chromosomal instability in meningiomas
Gilson S Baia1, Stefano Stifani, Edna T Kimura
1Brain Tumor Research Center, Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
Abstract:
The Notch signaling cascade is deregulated in diverse cancer types. Specific Notch function in cancer is dependent on the cellular context, the particular homologs expressed, and cross-talk with other signaling pathways. We have previously shown that components of the Notch signaling pathway are deregulated in meningiomas. However, the functional consequence of abnormal Notch signaling to meningiomas is unknown. Here, we report that exogenous expression of the Notch pathway effector, HES1, is associated with tetraploid cells in meningioma cell lines. Activated Notch1 and Notch2 receptors induced endogenous HES1 expression and were associated with tetraploidy in meningiomas. Tetraploid meningioma cells exhibited nuclear features of chromosomal instability and increased frequency of nuclear atypia, such as multipolar mitotic spindles and accumulation of cells with large nuclei. FACS-sorted tetraploid cells are viable but have higher rates of spontaneous apoptosis when compared with diploid cells. We have used spectral karyotyping to show that, in contrast to diploid cells, tetraploid cells develop a higher number of both numerical and structural chromosomal abnormalities. Our findings identify a novel function for the Notch signaling pathway in generating tetraploidy and contributing to chromosomal instability. We speculate that abnormal Notch signaling pathway is an initiating genetic mechanism for meningioma and potentially promotes tumor development.
Insights
Notch signaling pathway activation in meningiomas promotes tetraploidy and chromosomal instability. This suggests abnormal Notch signaling may initiate meningioma development and drive tumor progression.
Area of Science:
- Oncology
- Cell Biology
- Genetics
Background:
- Notch signaling pathway deregulation is implicated in various cancers.
- Previous studies identified deregulated Notch pathway components in meningiomas.
- The functional role of aberrant Notch signaling in meningioma pathogenesis remains unclear.
Purpose of the Study:
- To investigate the functional consequences of abnormal Notch signaling in meningiomas.
- To determine the association between Notch pathway activation and cellular changes in meningioma.
Main Methods:
- Analysis of HES1 expression in meningioma cell lines.
- Activation of Notch1 and Notch2 receptors.
- Flow cytometry analysis (FACS) of cell ploidy.
- Spectral karyotyping for chromosomal abnormality assessment.
- Microscopic evaluation of nuclear morphology and mitotic spindles.
Main Results:
- Exogenous HES1 expression correlated with tetraploidy in meningioma cell lines.
- Activated Notch1/Notch2 receptors induced HES1 and were linked to tetraploidy.
- Tetraploid meningioma cells displayed chromosomal instability and nuclear atypia.
- Tetraploid cells showed increased spontaneous apoptosis compared to diploid cells.
- Spectral karyotyping revealed higher numerical and structural chromosomal abnormalities in tetraploid cells.
Conclusions:
- The Notch signaling pathway generates tetraploidy and contributes to chromosomal instability in meningiomas.
- Aberrant Notch signaling may serve as an initiating genetic event in meningioma development.
- This pathway could play a role in promoting meningioma tumor progression.
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