Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome

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

doi:10.1038/bjc.2015.193

Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome

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

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

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 language	English (US)
Pages (from-to)	327-335
Number of pages	9
Journal	British journal of cancer
Volume	113
Issue number	2
DOIs	https://doi.org/10.1038/bjc.2015.193
State	Published - Jul 14 2015
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1038/bjc.2015.193

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@article{ca01ac801b0a4ae98ee8096cdc5eeb64,

title = "Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome",

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.",

author = "Wightman, {S. C.} and A. Uppal and Pitroda, {S. P.} and S. Ganai and B. Burnette and M. Stack and G. Oshima and S. Khan and X. Huang and Posner, {M. C.} and Weichselbaum, {R. R.} and Khodarev, {N. N.}",

note = "Funding Information: We thank Dr Samuel Hellman for his helpful discussions regarding this manuscript. This work was supported in part by The Virginia and DK Ludwig Fund for Cancer Research, Lung Cancer Research Foundation (LCRF), Prostate Cancer Foundation (PCF) and a generous gift from the Foglia family. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.",

year = "2015",

month = jul,

day = "14",

doi = "10.1038/bjc.2015.193",

language = "English (US)",

volume = "113",

pages = "327--335",

journal = "British journal of cancer",

issn = "0007-0920",

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T1 - Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome

AU - Wightman, S. C.

AU - Uppal, A.

AU - Pitroda, S. P.

AU - Ganai, S.

AU - Burnette, B.

AU - Stack, M.

AU - Oshima, G.

AU - Khan, S.

AU - Huang, X.

AU - Posner, M. C.

AU - Weichselbaum, R. R.

AU - Khodarev, N. N.

N1 - Funding Information: We thank Dr Samuel Hellman for his helpful discussions regarding this manuscript. This work was supported in part by The Virginia and DK Ludwig Fund for Cancer Research, Lung Cancer Research Foundation (LCRF), Prostate Cancer Foundation (PCF) and a generous gift from the Foglia family. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

PY - 2015/7/14

Y1 - 2015/7/14

N2 - 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.

AB - 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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JO - British journal of cancer

JF - British journal of cancer

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ER -

Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome

Abstract

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