Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function.
Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.
Department of Reproductive Medicine and 2 Department of Pathology, Moores University of California, San Diego Cancer Center, La Jolla, CA 92093.
Christine
C
Jean
Xiao Lei
XL
Chen
Ju-Ock
JO
Nam
Isabelle
I
Tancioni
Sean
S
Uryu
Christine
C
Lawson
Kristy K
KK
Ward
Colin T
CT
Walsh
Nichol L G
NL
Miller
Majid
M
Ghassemian
Patric
P
Turowski
Elisabetta
E
Dejana
Sara
S
Weis
David A
DA
Cheresh
David D
DD
Schlaepfer
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism* / Q000502:physiology; D015820:Cadherins / Q000378:metabolism* / Q000502:physiology; D002465:Cell Movement; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5