Preventing the activation or cycling of the Rap1 GTPase alters adhesion and cytoskeletal dynamics and blocks metastatic melanoma cell extravasation into the lungs.
The Rap1 GTPase is a master regulator of cell adhesion, polarity, and migration. We show that both blocking Rap1 activation and expressing a constitutively active form of Rap1 reduced the ability of B16F1 melanoma cells to extravasate from the microvasculature and form metastatic lesions in the lungs. This correlated with a decreased ability of the tumor cells to undergo transendothelial migration (TEM) in vitro and form dynamic, F-actin-rich pseudopodia that penetrate capillary endothelial walls in vivo. Using multiple tumor cell lines, we show that the inability to form these membrane protrusions, which likely promote TEM and extravasation, can be explained by altered adhesion dynamics and impaired cell polarization that result when Rap1 activation or cycling is perturbed. Thus, targeting Rap1 could be a useful approach for reducing the metastatic dissemination of tumor cells that undergo active TEM.
Freeman
Spencer A
SA
Departments of Cellular and Physiological Sciences and Microbiology and Immunology and I3 and CELL Research Groups, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
McLeod
Sarah J
SJ
Dukowski
Janet
J
Austin
Pamela
P
Lee
Crystal C Y
CC
Millen-Martin
Brandie
B
Kubes
Paul
P
McCafferty
Donna-Marie
DM
Gold
Michael R
MR
Roskelley
Calvin D
CD
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D003599:Cytoskeleton / Q000201:enzymology / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation; D022001:Focal Adhesions / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000517:prevention & control / Q000556:secondary*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000201:enzymology* / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D020827:rap1 GTP-Binding Proteins