Mitogen-induced defective mitosis transforms neural progenitor cells
Hiba K Omairi1, Cameron J Grisdale2, Mathieu Meode1
1Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
Background:
Chromosome instability (CIN) with recurrent copy number alterations is a feature of many solid tumors, including glioblastoma (GBM), yet the genes that regulate cell division are rarely mutated in cancers. Here, we show that the brain-abundant mitogen, platelet-derived growth factor-A (PDGFA) fails to induce the expression of kinetochore and spindle assembly checkpoint genes leading to defective mitosis in neural progenitor cells (NPCs).
Methods:
Using a recently reported in vitro model of the initiation of high-grade gliomas from murine NPCs, we investigated the immediate effects of PDGFA exposure on the nuclear and mitotic phenotypes and patterns of gene and protein expression in NPCs, a putative GBM cell of origin.
Results:
NPCs divided abnormally in defined media containing PDGFA with P53-dependent effects. In wild-type cells, defective mitosis was associated with P53 activation and cell death, but in some null cells, defective mitosis was tolerated. Surviving cells had unstable genomes and proliferated in the presence of PDGFA accumulating random and clonal chromosomal rearrangements. The outcome of this process was a population of tumorigenic NPCs with recurrent gains and losses of chromosomal regions that were syntenic to those recurrently gained and lost in human GBM. By stimulating proliferation without setting the stage for successful mitosis, PDGFA-transformed NPCs lacking P53 function.
Conclusions:
Our work describes a mechanism of transformation of NPCs by a brain-associated mitogen, raising the possibility that the unique genomic architecture of GBM is an adaptation to defective mitosis that ensures the survival of affected cells.
Insights
Platelet-derived growth factor-A (PDGFA) causes defective mitosis in neural progenitor cells (NPCs), leading to genomic instability and glioblastoma (GBM) development, particularly in P53-deficient cells.
Area of Science:
- Neuroscience
- Cancer Biology
- Genetics
Background:
- Chromosome instability (CIN) is common in glioblastoma (GBM) but underlying causes are unclear.
- Genes regulating cell division are rarely mutated in cancers.
- Platelet-derived growth factor-A (PDGFA), a brain mitogen, was investigated for its role in GBM initiation.
Purpose of the Study:
- To investigate the effects of PDGFA on neural progenitor cells (NPCs) as a model for GBM initiation.
- To understand how PDGFA influences mitosis, gene expression, and genomic stability in NPCs.
Main Methods:
- Utilized an in vitro model of high-grade glioma initiation from murine NPCs.
- Exposed NPCs to PDGFA and analyzed nuclear/mitotic phenotypes, gene, and protein expression.
- Assessed P53-dependent effects on mitosis and cell survival.
Main Results:
- PDGFA induced abnormal mitosis in NPCs, with P53-dependent outcomes.
- Defective mitosis led to cell death in wild-type cells but was tolerated in P53-null cells.
- Surviving P53-null cells accumulated chromosomal rearrangements, forming tumorigenic NPCs with GBM-like genomic alterations.
Conclusions:
- PDGFA can transform NPCs by causing defective mitosis and genomic instability, particularly in the absence of P53.
- The genomic architecture of GBM may be an adaptation to ensure survival despite mitotic errors.
- This study reveals a mechanism for NPC transformation by a brain-associated mitogen, offering insights into GBM pathogenesis.
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