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 and Kairbaan M. Hodivala-Dilke ()
Additional contact information
Tanguy Lechertier: John Vane Science Centre
Louise E. Reynolds: John Vane Science Centre
Hyojin Kim: Institute of Cancer Research
Ana Rita Pedrosa: John Vane Science Centre
Jesús Gómez-Escudero: John Vane Science Centre
José M. Muñoz-Félix: John Vane Science Centre
Silvia Batista: Doca de Pedrouços
Matthew Dukinfield: John Vane Science Centre
Fevzi Demircioglu: John Vane Science Centre
Ping Pui Wong: John Vane Science Centre
Kylie P. Matchett: University of Edinburgh
Neil C. Henderson: University of Edinburgh
Gabriela D’Amico: John Vane Science Centre
Maddy Parsons: Kings College London
Catherine Harwood: Queen Mary University of London
Pascal Meier: Institute of Cancer Research
Kairbaan M. Hodivala-Dilke: John Vane Science Centre

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16618-6

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