RT Journal Article
SR Electronic
T1 Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 4590
OP 4601
DO 10.1158/0008-5472.CAN-09-3414
VO 70
IS 11
A1 Freeman, Spencer A.
A1 McLeod, Sarah J.
A1 Dukowski, Janet
A1 Austin, Pamela
A1 Lee, Crystal C.Y.
A1 Millen-Martin, Brandie
A1 Kubes, Paul
A1 McCafferty, Donna-Marie
A1 Gold, Michael R.
A1 Roskelley, Calvin D.
YR 2010
UL http://cancerres.aacrjournals.org/content/70/11/4590.abstract
AB 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. Cancer Res; 70(11); 4590–601. ©2010 AACR.©2010 American Association for Cancer Research.