Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth

Tanguy Lechertier, Louise E. Reynolds, Hyojin Kim, Ana Rita Pedrosa, Jesús Gómez-Escudero, José M Muñoz-Félix, Silvia Batista, Matthew Dukinfield, Fevzi Demircioglu, Ping Pui Wong, Kylie P. Matchett, Neil C. Henderson, Gabriela D'Amico, Maddy Parsons, Catherine Harwood, Pascal Meier, Kairbaan M. Hodivala-Dilke

Research output: Contribution to journalArticlepeer-review

Abstract

The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.

Original languageEnglish
Article number2810
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 4 Jun 2020

Keywords

  • Animals
  • Aorta, Thoracic/pathology
  • Carcinoma, Lewis Lung/metabolism
  • Cell Adhesion
  • Cell Proliferation
  • Cysteine-Rich Protein 61/metabolism
  • Female
  • Focal Adhesion Kinase 1/genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Lymphokines/metabolism
  • Male
  • Melanoma/blood supply
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms/pathology
  • Neovascularization, Pathologic
  • Pericytes/metabolism
  • Placenta Growth Factor/metabolism
  • Platelet-Derived Growth Factor/metabolism
  • Proto-Oncogene Proteins/metabolism
  • Proto-Oncogene Proteins c-sis/metabolism
  • Receptor Protein-Tyrosine Kinases/metabolism
  • Signal Transduction
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A/metabolism

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