Charan Kajal, Kar Sandip
Department of Chemistry, IIT Bombay, Powai, Mumbai 400076, India.
iScience. 2025 Jun 21;28(7):112981. doi: 10.1016/j.isci.2025.112981. eCollection 2025 Jul 18.
Cell cycle duration heterogeneities within a malignant tumor significantly reduce the therapeutic efficacy of cancer treatment. However, identifying factors governing such heterogeneities remains challenging. Herein, we perform a computational modeling study to demonstrate that correlated fluctuations of the inherited transcription rates during cell cycle progression and their random resetting in mitosis are sufficient to account for the experimentally observed cell cycle duration correlation patterns for cell lineage pairs. The model elucidates that the variations in the transcriptional inheritance pattern dictate the extent of the cousin-mother inequality phenomenon in a cell-type-dependent manner. Intriguingly, the model predicts that a reduction in cousin-mother inequality for a fixed mean cell cycle duration can lead to a lowering of the cell cycle duration variabilities at the population level which may have a therapeutic implication. Overall, our study elucidates that correlated transcriptional fluctuations can be the sole governing factor in orchestrating the cell cycle duration heterogeneities.
恶性肿瘤内的细胞周期持续时间异质性显著降低了癌症治疗的疗效。然而，确定控制这种异质性的因素仍然具有挑战性。在此，我们进行了一项计算建模研究，以证明细胞周期进程中遗传转录速率的相关波动及其在有丝分裂中的随机重置足以解释实验观察到的细胞谱系对的细胞周期持续时间相关模式。该模型阐明，转录遗传模式的变化以细胞类型依赖的方式决定了姐妹细胞 - 母细胞不平等现象的程度。有趣的是，该模型预测，在固定的平均细胞周期持续时间下，姐妹细胞 - 母细胞不平等的减少可能导致群体水平上细胞周期持续时间变异性的降低，这可能具有治疗意义。总体而言，我们的研究阐明，相关的转录波动可能是协调细胞周期持续时间异质性的唯一控制因素。
