Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
Canada's Michael Smith Genome Sciences Centre and BC Cancer, University of British Columbia, Vancouver, British Columbia, Canada.
Neuro Oncol. 2023 Oct 3;25(10):1763-1774. doi: 10.1093/neuonc/noad082.
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).
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.
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.
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.
染色体不稳定（CIN）伴有反复的拷贝数改变是许多实体瘤的特征，包括胶质母细胞瘤（GBM），然而，调节细胞分裂的基因在癌症中很少发生突变。在这里，我们表明，脑丰富的有丝分裂原血小板衍生生长因子-A（PDGFA）未能诱导动粒和纺锤体组装检查点基因的表达，导致神经祖细胞（NPC）有缺陷的有丝分裂。
使用最近报道的从鼠 NPC 中起始高级别神经胶质瘤的体外模型，我们研究了 PDGFA 暴露对 NPC 核和有丝分裂表型以及基因和蛋白表达模式的即时影响，NPC 是 GBM 的起源细胞。
NPC 在含有 PDGFA 的特定培养基中异常分裂，具有 P53 依赖性效应。在野生型细胞中，有缺陷的有丝分裂与 P53 激活和细胞死亡有关，但在一些缺失细胞中，有缺陷的有丝分裂是可以耐受的。存活的细胞具有不稳定的基因组，并在 PDGFA 存在下增殖，积累随机和克隆染色体重排。这个过程的结果是产生了一群具有肿瘤发生潜力的 NPC，其染色体区域的增益和缺失与人类 GBM 中反复获得和丢失的区域具有同源性。通过刺激增殖而不设定成功有丝分裂的阶段，PDGFA 转化的 NPC 缺乏 P53 功能。
我们的工作描述了一种由脑相关有丝分裂原诱导 NPC 转化的机制，这提出了一种可能性，即 GBM 的独特基因组结构是对有缺陷的有丝分裂的一种适应，确保了受影响细胞的存活。
