Research ArticleCell Biology

Short-term cellular memory tunes the signaling responses of the chemokine receptor CXCR4

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Science Signaling  09 Jul 2019:
Vol. 12, Issue 589, eaaw4204
DOI: 10.1126/scisignal.aaw4204

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Remembering the past for CXCR4 signaling

Activation of the chemokine receptor CXCR4 by its ligand CXCL12 enables cancer cells to disseminate and metastasize. Spinosa et al. performed imaging analysis and computational modeling to analyze signaling responses mediated by CXCR4 at the single-cell level. CXCR4 can signal through the kinases Akt and ERK. The authors found that exposing cells to different growth-promoting stimuli before CXCL12 altered the activity of upstream kinases (PI3K and Ras) or of a common downstream kinase complex (mTORC1) to bias CXCR4 signaling through either Akt or ERK. Furthermore, kinase inhibitors that are clinically used to treat cancer increased the likelihood of CXCR4 activation of Akt and/or ERK, suggesting that such drugs may inadvertently promote pro-metastatic CXCR4 signaling.


The chemokine receptor CXCR4 regulates fundamental processes in development, normal physiology, and diseases, including cancer. Small subpopulations of CXCR4-positive cells drive the local invasion and dissemination of malignant cells during metastasis, emphasizing the need to understand the mechanisms controlling responses at the single-cell level to receptor activation by the chemokine ligand CXCL12. Using single-cell imaging, we discovered that short-term cellular memory of changes in environmental conditions tuned CXCR4 signaling to Akt and ERK, two kinases activated by this receptor. Conditioning cells with growth stimuli before CXCL12 exposure increased the number of cells that initiated CXCR4 signaling and the amplitude of Akt and ERK activation. Data-driven, single-cell computational modeling revealed that growth factor conditioning modulated CXCR4-dependent activation of Akt and ERK by decreasing extrinsic noise (preexisting cell-to-cell differences in kinase activity) in PI3K and mTORC1. Modeling established mTORC1 as critical for tuning single-cell responses to CXCL12-CXCR4 signaling. Our single-cell model predicted how combinations of extrinsic noise in PI3K, Ras, and mTORC1 superimposed on different driver mutations in the ERK and/or Akt pathways to bias CXCR4 signaling. Computational experiments correctly predicted that selected kinase inhibitors used for cancer therapy shifted subsets of cells to states that were more permissive to CXCR4 activation, suggesting that such drugs may inadvertently potentiate pro-metastatic CXCR4 signaling. Our work establishes how changing environmental inputs modulate CXCR4 signaling in single cells and provides a framework to optimize the development and use of drugs targeting this signaling pathway.

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