Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
NPJ Syst Biol Appl. 2024 Jun 4;10(1):65. doi: 10.1038/s41540-024-00389-7.
Understanding the dynamics of intracellular signaling pathways, such as ERK1/2 (ERK) and Akt1/2 (Akt), in the context of cell fate decisions is important for advancing our knowledge of cellular processes and diseases, particularly cancer. While previous studies have established associations between ERK and Akt activities and proliferative cell fate, the heterogeneity of single-cell responses adds complexity to this understanding. This study employed a data-driven approach to address this challenge, developing machine learning models trained on a dataset of growth factor-induced ERK and Akt activity time courses in single cells, to predict cell division events. The most predictive models were developed by applying discrete wavelet transforms (DWTs) to extract low-frequency features from the time courses, followed by using Ensemble Integration, a data integration and predictive modeling framework. The results demonstrated that these models effectively predicted cell division events in MCF10A cells (F-measure=0.524, AUC=0.726). ERK dynamics were found to be more predictive than Akt, but the combination of both measurements further enhanced predictive performance. The ERK model`s performance also generalized to predicting division events in RPE cells, indicating the potential applicability of these models and our data-driven methodology for predicting cell division across different biological contexts. Interpretation of these models suggested that ERK dynamics throughout the cell cycle, rather than immediately after growth factor stimulation, were associated with the likelihood of cell division. Overall, this work contributes insights into the predictive power of intra-cellular signaling dynamics for cell fate decisions, and highlights the potential of machine learning approaches in unraveling complex cellular behaviors.
理解细胞命运决策中细胞内信号通路(如 ERK1/2(ERK)和 Akt1/2(Akt))的动态对于推进我们对细胞过程和疾病(尤其是癌症)的认识非常重要。虽然先前的研究已经确定了 ERK 和 Akt 活性与增殖细胞命运之间的关联,但单细胞反应的异质性增加了对此理解的复杂性。本研究采用数据驱动的方法来解决这一挑战,开发了基于生长因子诱导的 ERK 和 Akt 活性时间序列的单细胞数据集的机器学习模型,以预测细胞分裂事件。最具预测性的模型是通过对时间序列进行离散小波变换(DWT)提取低频特征,然后应用 Ensemble Integration(一种数据集成和预测建模框架)来开发的。结果表明,这些模型有效地预测了 MCF10A 细胞的细胞分裂事件(F 度量=0.524,AUC=0.726)。ERK 动力学比 Akt 更具预测性,但两者的组合进一步提高了预测性能。ERK 模型的性能也可以推广到预测 RPE 细胞的分裂事件,表明这些模型和我们的数据驱动方法在预测不同生物学背景下的细胞分裂方面具有潜在的适用性。对这些模型的解释表明,ERK 动力学在整个细胞周期中,而不是在生长因子刺激后立即,与细胞分裂的可能性相关。总的来说,这项工作为细胞命运决策中细胞内信号动态的预测能力提供了新的见解,并强调了机器学习方法在揭示复杂细胞行为方面的潜力。