Introduction

CXCR4 and epidermal growth factor receptor (EGFR) represent two major families of receptors, G-protein coupled receptors and receptor tyrosine kinases, with central functions in cancer. While utilizing different upstream signaling molecules, both CXCR4 and EGFR activate kinases ERK and Akt, although single-cell activation of these kinases is markedly heterogeneous. One hypothesis regarding the origin of signaling heterogeneity proposes that intercellular variations arise from differences in pre-existing intracellular states set by extrinsic noise. While pre-existing cell states vary among cells, each pre-existing state defines deterministic signaling outputs to downstream effectors. Understanding causes of signaling heterogeneity will inform treatment of cancers with drugs targeting drivers of oncogenic signaling.

Methods

We built a single-cell computational model to predict Akt and ERK responses to CXCR4- and EGFR-mediated stimulation. We investigated signaling heterogeneity through these receptors and tested model predictions using quantitative, live-cell time-lapse imaging.

Results

We show that the pre-existing cell state predicts single-cell signaling through both CXCR4 and EGFR. Computational modeling reveals that the same set of pre-existing cell states explains signaling heterogeneity through both EGFR and CXCR4 at multiple doses of ligands and in two different breast cancer cell lines. The model also predicts how phosphatidylinositol-3-kinase (PI3K) targeted therapies potentiate ERK signaling in certain breast cancer cells and that low level, combined inhibition of MEK and PI3K ablates potentiated ERK signaling.

Conclusions

Our data demonstrate that a conserved motif exists for EGFR and CXCR4 signaling and suggest potential clinical utility of the computational model to optimize therapy.

中文翻译：

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预先存在的细胞状态控制 EGFR 和 CXCR4 信号传导的异质性

介绍

CXCR4 和表皮生长因子受体 (EGFR) 代表两个主要受体家族：G 蛋白偶联受体和受体酪氨酸激酶，在癌症中具有核心功能。虽然利用不同的上游信号分子，CXCR4 和 EGFR 均激活激酶 ERK 和 Akt，尽管这些激酶的单细胞激活具有明显的异质性。关于信号传导异质性起源的一种假设提出，细胞间变异是由外部噪声设定的预先存在的细胞内状态的差异引起的。虽然预先存在的细胞状态因细胞而异，但每个预先存在的状态都定义了到下游效应器的确定性信号输出。了解信号异质性的原因将为使用针对致癌信号驱动因素的药物治疗癌症提供信息。

方法

我们建立了一个单细胞计算模型来预测 Akt 和 ERK 对 CXCR4 和 EGFR 介导的刺激的反应。我们研究了这些受体的信号异质性，并使用定量活细胞延时成像测试了模型预测。

结果

我们表明，预先存在的细胞状态通过 CXCR4 和 EGFR 预测单细胞信号传导。计算模型表明，同一组预先存在的细胞状态解释了在多种配体剂量和两种不同乳腺癌细胞系中通过 EGFR 和 CXCR4 发出的信号异质性。该模型还预测磷脂酰肌醇-3-激酶 (PI3K) 靶向治疗如何增强某些乳腺癌细胞中的 ERK 信号传导，以及 MEK 和 PI3K 的低水平联合抑制如何消除增强的 ERK 信号传导。

结论

我们的数据表明 EGFR 和 CXCR4 信号传导存在保守基序，并表明计算模型在优化治疗方面具有潜在的临床效用。