Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth
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 angioge...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2020-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-020-16618-6 |
| _version_ | 1797689107253559296 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Tanguy Lechertier |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T01:41:16Z |
| format | Article |
| id | doaj.art-327b0c1e155a4263840ab94acda7cb38 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T01:41:16Z |
| publishDate | 2020-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-327b0c1e155a4263840ab94acda7cb382023-09-10T11:17:18ZengNature PortfolioNature Communications2041-17232020-06-0111111410.1038/s41467-020-16618-6Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growthTanguy Lechertier0Louise E. Reynolds1Hyojin Kim2Ana Rita Pedrosa3Jesús Gómez-Escudero4José M. Muñoz-Félix5Silvia Batista6Matthew Dukinfield7Fevzi Demircioglu8Ping Pui Wong9Kylie P. Matchett10Neil C. Henderson11Gabriela D’Amico12Maddy Parsons13Catherine Harwood14Pascal Meier15Kairbaan M. Hodivala-Dilke16Centre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreCell Death & Inflammation, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer ResearchCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreSystems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown Av. Brasília, Doca de PedrouçosCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreCentre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of EdinburghCentre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of EdinburghCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreNikon Imaging Centre@King’s, Randall Division of Cell and Molecular Biophysics, Kings College LondonCentre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of LondonCell Death & Inflammation, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer ResearchCentre for Tumour Biology, Barts Cancer Institute – a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science CentreAbstract 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.https://doi.org/10.1038/s41467-020-16618-6 |
| spellingShingle | 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 Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth Nature Communications |
| title | Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth |
| title_full | Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth |
| title_fullStr | Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth |
| title_full_unstemmed | Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth |
| title_short | Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth |
| title_sort | pericyte fak negatively regulates gas6 axl signalling to suppress tumour angiogenesis and tumour growth |
| url | https://doi.org/10.1038/s41467-020-16618-6 |
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