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

doi:10.1038/s41467-020-16618-6

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 journal › Article › peer-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 language	English
Article number	2810
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-16618-6
Publication status	Published - 4 Jun 2020

Keywords / Materials (for Non-textual outputs)

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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10.1038/s41467-020-16618-6Licence: Creative Commons: Attribution (CC-BY)

Henderson N Pericyte FAK...
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
Final published version, 5.76 MBLicence: Creative Commons: Attribution (CC-BY)

Neil Henderson
- Neil.Hendersoned.acuk
- Deanery of Clinical Sciences - Personal Chair of Tissue Repair and Regeneration
- Centre for Inflammation Research
Person: Academic: Research Active (Research Assistant)

Cite this

Lechertier, T., Reynolds, L. E., Kim, H., Pedrosa, A. R., Gómez-Escudero, J., Muñoz-Félix, J. M., Batista, S., Dukinfield, M., Demircioglu, F., Wong, P. P., Matchett, K. P., Henderson, N. C., D'Amico, G., Parsons, M., Harwood, C., Meier, P., & Hodivala-Dilke, K. M. (2020). Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth. Nature Communications, 11, Article 2810. https://doi.org/10.1038/s41467-020-16618-6

@article{e5dbbfdacedc45b1a7137888ccb0618c,

title = "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 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.",

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",

author = "Tanguy Lechertier and Reynolds, {Louise E.} and Hyojin Kim and Pedrosa, {Ana Rita} and Jes{\'u}s G{\'o}mez-Escudero and Mu{\~n}oz-F{\'e}lix, {Jos{\'e} M} and Silvia Batista and Matthew Dukinfield and Fevzi Demircioglu and Wong, {Ping Pui} and Matchett, {Kylie P.} and Henderson, {Neil C.} and Gabriela D'Amico and Maddy Parsons and Catherine Harwood and Pascal Meier and Hodivala-Dilke, {Kairbaan M.}",

year = "2020",

month = jun,

day = "4",

doi = "10.1038/s41467-020-16618-6",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Lechertier, T, Reynolds, LE, Kim, H, Pedrosa, AR, Gómez-Escudero, J, Muñoz-Félix, JM, Batista, S, Dukinfield, M, Demircioglu, F, Wong, PP, Matchett, KP , Henderson, NC, D'Amico, G, Parsons, M, Harwood, C, Meier, P & Hodivala-Dilke, KM 2020, 'Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth', Nature Communications, vol. 11, 2810. https://doi.org/10.1038/s41467-020-16618-6

TY - JOUR

T1 - Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth

AU - Lechertier, Tanguy

AU - Reynolds, Louise E.

AU - Kim, Hyojin

AU - Pedrosa, Ana Rita

AU - Gómez-Escudero, Jesús

AU - Muñoz-Félix, José M

AU - Batista, Silvia

AU - Dukinfield, Matthew

AU - Demircioglu, Fevzi

AU - Wong, Ping Pui

AU - Matchett, Kylie P.

AU - Henderson, Neil C.

AU - D'Amico, Gabriela

AU - Parsons, Maddy

AU - Harwood, Catherine

AU - Meier, Pascal

AU - Hodivala-Dilke, Kairbaan M.

PY - 2020/6/4

Y1 - 2020/6/4

N2 - 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.

AB - 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.

KW - Animals

KW - Aorta, Thoracic/pathology

KW - Carcinoma, Lewis Lung/metabolism

KW - Cell Adhesion

KW - Cell Proliferation

KW - Cysteine-Rich Protein 61/metabolism

KW - Female

KW - Focal Adhesion Kinase 1/genetics

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Intercellular Signaling Peptides and Proteins/metabolism

KW - Lymphokines/metabolism

KW - Male

KW - Melanoma/blood supply

KW - Melanoma, Experimental

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neoplasms/pathology

KW - Neovascularization, Pathologic

KW - Pericytes/metabolism

KW - Placenta Growth Factor/metabolism

KW - Platelet-Derived Growth Factor/metabolism

KW - Proto-Oncogene Proteins/metabolism

KW - Proto-Oncogene Proteins c-sis/metabolism

KW - Receptor Protein-Tyrosine Kinases/metabolism

KW - Signal Transduction

KW - Tumor Microenvironment

KW - Vascular Endothelial Growth Factor A/metabolism

U2 - 10.1038/s41467-020-16618-6

DO - 10.1038/s41467-020-16618-6

M3 - Article

C2 - 32499572

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 2810

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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Neil Henderson

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