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

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

doi:10.1038/s41467-020-16618-6

Cited by 40 publications

(36 citation statements)

References 51 publications

(56 reference statements)

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“…Mechanistically, the loss of pericyte FAK enhanced the expression of the proangiogenic and tumorigenic cytokine Cyr61, via a Gas6/Axl axis, driving tumour progression. These results were corroborated by human melanoma studies, where a high correlation was shown between tumour size and loss of pericyte-FAK [ 19 ]. As in ECs, pericyte FAK phosphorylation appears to have distinct roles in tumour growth and angiogenesis.…”

Section: Adhesome Function In Vasculaturesupporting

confidence: 65%

“…Recent studies using genetic deletion approaches have addressed the role of mural FAK in tumour angiogenesis and cancer development. In particular, mural FAK deficiency enhanced tumour growth and angiogenesis in syngeneic subcutaneous mouse models and spontaneously arising RIP-Tag2 pancreatic tumours [ 19 ]. In both models, FAK deficiency weakened the association of pericytes with tumour blood vessels and increased tumour angiogenesis.…”

Section: Adhesome Function In Vasculaturementioning

confidence: 99%

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The Adhesome Network: Key Components Shaping the Tumour Stroma

Nikolopoulou

Koufaki

Kostourou

2021

Cancers

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Beyond the conventional perception of solid tumours as mere masses of cancer cells, advanced cancer research focuses on the complex contributions of tumour-associated host cells that are known as “tumour microenvironment” (TME). It has been long appreciated that the tumour stroma, composed mainly of blood vessels, cancer-associated fibroblasts and immune cells, together with the extracellular matrix (ECM), define the tumour architecture and influence cancer cell properties. Besides soluble cues, that mediate the crosstalk between tumour and stroma cells, cell adhesion to ECM arises as a crucial determinant in cancer progression. In this review, we discuss how adhesome, the intracellular protein network formed at cell adhesions, regulate the TME and control malignancy. The role of adhesome extends beyond the physical attachment of cells to ECM and the regulation of cytoskeletal remodelling and acts as a signalling and mechanosensing hub, orchestrating cellular responses that shape the tumour milieu.

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Section: Adhesome Function In Vasculaturesupporting

confidence: 65%

Section: Adhesome Function In Vasculaturementioning

confidence: 99%

The Adhesome Network: Key Components Shaping the Tumour Stroma

Nikolopoulou

Koufaki

Kostourou

2021

Cancers

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“…Our data demonstrate that FAK-Y861F pericytes decrease tumour burden, at least in part, by directly affecting tumour cell apoptosis, and call for further consideration of the role of tumour pericytes in the direct control of tumour growth, in addition to their effects on vessel stabilisation. Indeed, we have recently shown that pericytes play a central role in the control of primary tumour growth, through cross-talk with multiple cell types in the tumour microenvironment [19,20]. FAK is upregulated in many cancer types and is currently being targeted as a potential anti-cancer agent because of its essential roles in tumour growth and angiogenesis [12,[32][33][34].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, we have shown that non-phosphorylatable mutations of tyrosines 397 and 861 (Y397 and Y861) in endothelial cells have differential effects on tumour angiogenesis [17] and that endothelial cell FAK regulates angiocrine signalling in the control of doxorubicin sensitivity in malignant cells [18]. Whilst FAK has been studied extensively in endothelial cells, the function of FAK in pericytes during tumour growth and angiogenesis is starting to emerge, with loss of pericyte FAK enhancing tumour angiogenesis [19]. Given that pericytes are an important cell type in the regulation of tumour growth and paracrine signalling [20][21][22], here we have examined the role of FAK point mutations in pericytes during pathological angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

et al. 2021

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY397F/Y397F and PdgfrβCre + ;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ;FAKY861F/Y861F but not PdgfrβCre + ;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

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“…For instance, the deletion of endothelial FAK in vivo reduced the vascular–endothelial growth factor (VEGF)-dependent neovascularization and inhibited the tumor growth and angiogenesis in adult mouse models [ 166 ]. Endothelial FAK has also been involved in the resistance to both irradiation and DNA-damaging therapies and in the dysregulated cross-talk between ECs and pericytes that may lead to the instability of the tumor microvasculature and influence the tumor growth [ 167 , 168 ].…”

Section: Fak and The Breast Tmementioning

confidence: 99%

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

Rigiracciolo

Cirillo

Talia

et al. 2021

Cancers

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Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors.

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

Cited by 40 publications

References 51 publications

The Adhesome Network: Key Components Shaping the Tumour Stroma

The Adhesome Network: Key Components Shaping the Tumour Stroma

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

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