The CXCL12/CXCR7 signaling axis, isoforms, circadian rhythms, and tumor cellular composition dictate gradients in tissue

Spinosa, Phillip C.; Luker, Gary D.; Linderman, Jennifer J.

doi:10.1371/journal.pone.0187357

Cited by 11 publications

(7 citation statements)

References 47 publications

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“…CXCL12 is a ubiquitous chemokine whose expression is regulated by circadian signals (251) and inflammatory mediators. Based on its essential role in embryogenesis and in homeostasis, it has been traditionally classified as a homeostatic chemokine.…”

Section: Summary/perspectivesmentioning

confidence: 99%

The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases

et al. 2019

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Chemokine receptors are members of the G protein-coupled receptor superfamily. These receptors are intimately involved in cell movement, and thus play a critical role in several physiological and pathological situations that require the precise regulation of cell positioning. CXCR4 is one of the most studied chemokine receptors and is involved in many functions beyond leukocyte recruitment. During embryogenesis, it plays essential roles in vascular development, hematopoiesis, cardiogenesis, and nervous system organization. It has been also implicated in tumor progression and autoimmune diseases and, together with CD4, is one of the co-receptors used by the HIV-1 virus to infect immune cells. In contrast to other chemokine receptors that are characterized by ligand promiscuity, CXCR4 has a unique ligand—stromal cell-derived factor-1 (SDF1, CXCL12). However, this ligand also binds ACKR3, an atypical chemokine receptor that modulates CXCR4 functions and is overexpressed in multiple cancer types. The CXCL12/CXCR4/ACKR3 axis constitutes a potential therapeutic target for a wide variety of inflammatory diseases, not only by interfering with cell migration but also by modulating immune responses. Thus far, only one antagonist directed against the ligand-binding site of CXCR4, AMD3100, has demonstrated clinical relevance. Here, we review the role of this ligand and its receptors in different autoimmune diseases.

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Section: Summary/perspectivesmentioning

confidence: 99%

The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases

et al. 2019

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“…Receptor dynamics (CXCR4 trafficking after CXCL12 stimulation) are as described previously (35)(36)(37). Briefly, CXCL12 in the extracellular space binds to CXCR4.…”

Section: Computational Model: Receptor Dynamicsmentioning

confidence: 99%

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

et al. 2019

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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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“…Due to the binding with the extracellular matrix, CXCL12 is protected from cell degradation process and consequently has a slower tissues release. This mechanism leads to the formation of specific gradients based on the different affinities of isoforms ECM binding [37, 62].…”

Section: Cxcl12 Isoformsmentioning

confidence: 99%

CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Righetti¹,

Giulietti²,

Sabanovic³

et al. 2019

Journal of Oncology

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CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

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The CXCL12/CXCR7 signaling axis, isoforms, circadian rhythms, and tumor cellular composition dictate gradients in tissue

Cited by 11 publications

References 47 publications

The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases

The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases

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

CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

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