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

Author:

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

Abstract

AbstractThe 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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