CXCR4 signaling regulates metastatic onset by controlling neutrophil motility and response to malignant cells

Scientific Reports
Claudia TulottaB Ewa Snaar-Jagalska

Abstract

Developing tumors interact with the surrounding microenvironment. Myeloid cells exert both anti- and pro-tumor functions and chemokines are known to drive immune cell migration towards cancer cells. It is documented that CXCR4 signaling supports tumor metastasis formation in tissues where CXCL12, its cognate ligand, is abundant. On the other hand, the role of the neutrophilic CXCR4 signaling in driving cancer invasion and metastasis formation is poorly understood. Here, we use the zebrafish xenotransplantation model to study the role of CXCR4 signaling in driving the interaction between invasive human tumor cells and host neutrophils, supporting early metastasis formation. We found that zebrafish cxcr4 (cxcr4b) is highly expressed in neutrophils and experimental micrometastases fail to form in mutant larvae lacking a functional Cxcr4b. We demonstrated that Cxcr4b controls neutrophil number and motility and showed that Cxcr4b transcriptomic signature relates to motility and adhesion regulation in neutrophils in tumor-naïve larvae. Finally, Cxcr4b deficient neutrophils failed to interact with cancer cells initiating early metastatic events. In conclusion, we propose that CXCR4 signaling supports the interaction between tumor cell...Continue Reading

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Citations

Oct 17, 2019·Cold Spring Harbor Perspectives in Medicine·Katy R Astell, Dirk Sieger
Aug 18, 2020·Journal of Inflammation Research·Yanwen PengHaijin Lv
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Aug 18, 2021·Molecular Therapy. Nucleic Acids·Weiwei ZhuangKeqing Shi

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Methods Mentioned

BETA
xenograft
gene knock-down
transgenic
PCR
FCS
Chip
Illumina sequencing

Software Mentioned

GraphPad Prism
LAS AF Lite
Bioconductor
DESeq
BD FACSDiva
Elements AR
DESeq2
EdgeR
ImageJ
R Studio

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