Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome

S. C. Wightman, A. Uppal, S. P. Pitroda, S. Ganai, B. Burnette, M. Stack, Go Oshima, S. Khan, X. Huang, M. C. Posner, R. R. Weichselbaum, N. N. Khodarev

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background:The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones.Methods:We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas.Results:We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival.Conclusion:These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease.

Original languageEnglish
Pages (from-to)327-335
Number of pages9
JournalBritish Journal of Cancer
Volume113
Issue number2
DOIs
Publication statusPublished - 2015 Jul 14
Externally publishedYes

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Neoplasm Metastasis
Melanoma
Neoplasms
Paracrine Communication
Stromal Cells
Renal Cell Carcinoma
Small Interfering RNA
Cell Movement
Disease Progression
Colon
Leukocytes
Clone Cells
Cytokines
Recurrence
Survival
Growth
Datasets
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wightman, S. C., Uppal, A., Pitroda, S. P., Ganai, S., Burnette, B., Stack, M., ... Khodarev, N. N. (2015). Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome. British Journal of Cancer, 113(2), 327-335. https://doi.org/10.1038/bjc.2015.193

Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome. / Wightman, S. C.; Uppal, A.; Pitroda, S. P.; Ganai, S.; Burnette, B.; Stack, M.; Oshima, Go; Khan, S.; Huang, X.; Posner, M. C.; Weichselbaum, R. R.; Khodarev, N. N.

In: British Journal of Cancer, Vol. 113, No. 2, 14.07.2015, p. 327-335.

Research output: Contribution to journalArticle

Wightman, SC, Uppal, A, Pitroda, SP, Ganai, S, Burnette, B, Stack, M, Oshima, G, Khan, S, Huang, X, Posner, MC, Weichselbaum, RR & Khodarev, NN 2015, 'Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome', British Journal of Cancer, vol. 113, no. 2, pp. 327-335. https://doi.org/10.1038/bjc.2015.193
Wightman SC, Uppal A, Pitroda SP, Ganai S, Burnette B, Stack M et al. Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome. British Journal of Cancer. 2015 Jul 14;113(2):327-335. https://doi.org/10.1038/bjc.2015.193
Wightman, S. C. ; Uppal, A. ; Pitroda, S. P. ; Ganai, S. ; Burnette, B. ; Stack, M. ; Oshima, Go ; Khan, S. ; Huang, X. ; Posner, M. C. ; Weichselbaum, R. R. ; Khodarev, N. N. / Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome. In: British Journal of Cancer. 2015 ; Vol. 113, No. 2. pp. 327-335.
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abstract = "Background:The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones.Methods:We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas.Results:We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival.Conclusion:These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease.",
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AU - Stack, M.

AU - Oshima, Go

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