Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration

Hasini Jayatilaka, Pranay Tyle, Jonathan J. Chen, Minsuk Kwak, Julia Ju, Hyun Ji Kim, Jerry S.H. Lee, Pei Hsun Wu, Daniele M. Gilkes, Rong Fan, Denis Wirtz

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Abstract

Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells- but not in normal or non-metastatic cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells.

Original languageEnglish
Article number15584
JournalNature communications
Volume8
DOIs
Publication statusPublished - 2017 May 26

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Jayatilaka, H., Tyle, P., Chen, J. J., Kwak, M., Ju, J., Kim, H. J., Lee, J. S. H., Wu, P. H., Gilkes, D. M., Fan, R., & Wirtz, D. (2017). Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration. Nature communications, 8, [15584]. https://doi.org/10.1038/ncomms15584