TNF-receptor-1 adaptor protein FAN mediates TNF-induced B16 melanoma motility and invasion

Br J Cancer. 2013 Jul 23;109(2):422-32. doi: 10.1038/bjc.2013.242. Epub 2013 May 14.


Background: Locomotion of cancer cells can be induced by TNF and other motogenic factors secreted by cells of the tumour microenvironment such as macrophages. Based on our recent findings that the TNF receptor adaptor protein FAN mediates TNF-induced actin reorganisation and regulates the directed migration of immune cells responding to chemotactic cues, we addressed the role of FAN in cancer cell motility and the formation of invadopodia, a crucial feature in tumour invasion.

Methods: In B16 mouse melanoma cells, FAN was downregulated and the impact on FAN on cell motility and invasion was determined using in vitro assays and in vivo animal models.

Results: Like FAN(-/-) murine embryonic fibroblasts, FAN-deficient B16 melanoma cells showed defective motility responses to TNF in vitro. In vivo FAN-deficient B16 melanoma cells produced significantly less disseminated tumours after i.v. injection into mice. Danio rerio used as a second in vivo model also revealed impaired spreading of FAN-deficient B16 melanoma cells. Furthermore, FAN mediated TNF-induced paxillin phosphorylation, metalloproteinase activation and increased extracellular matrix degradation, the hallmarks of functionally active invadopodia.

Conclusion: The results of our study suggest that FAN through promoting melanoma cellular motility and tumour invasiveness is critical for the tumour-promoting action of TNF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Cell Movement / drug effects
  • Cell Movement / genetics*
  • Cells, Cultured
  • Female
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Melanoma, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Invasiveness
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / drug effects
  • Skin Neoplasms / pathology*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Nsmaf protein, mouse
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha