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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Wightman
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: A
authors.initials: A
authors.lastname: Uppal
authors.affiliation: 1] Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA [2] Ludwig Center for Metastasis Research, University of Chicago, 5841 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Pitroda
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ganai
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: B
authors.initials: B
authors.lastname: Burnette
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: M
authors.initials: M
authors.lastname: Stack
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: G
authors.initials: G
authors.lastname: Oshima
authors.affiliation: Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.affiliation: 1] Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA [2] Ludwig Center for Metastasis Research, University of Chicago, 5841 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: 1] Department of Surgery, University of Chicago, Chicago, IL 60637, USA [2] Ludwig Center for Metastasis Research, University of Chicago, 5841 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Posner
authors.affiliation: 1] Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA [2] Ludwig Center for Metastasis Research, University of Chicago, 5841 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: 1] Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA [2] Ludwig Center for Metastasis Research, University of Chicago, 5841 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA.
authors.forename: N N
authors.initials: NN
authors.lastname: Khodarev
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D054367:Receptors, CXCR3 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054367:Receptors, CXCR3