AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

// Laura M. Divine 1, * , Mai R. Nguyen 1, * , Eric Meller 1 , Riva A. Desai 1 , Batool Arif 1 , Erinn B. Rankin 2, 3 , Katherine H. Bligard 1 , Cherise Meyerson 4 , Ian S. Hagemann 1, 4 , Maria Massad 1 , Premal H. Thaker 1 , Andrea R. Hagemann 1 , Carolyn K. McCourt 1 , Matt A. Powell 1 , David G. Mutch 1 , Katherine C. Fuh 1, 5 1 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA 2 Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA, USA 3 Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, CA, USA 4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 5 Center for Reproductive Health Sciences (CRepHS), Washington University in St. Louis, St. Louis, MO, USA * These authors have contributed equally to this work Correspondence to: Katherine C. Fuh, email: kfuh@wudosis.wustl.edu Keywords: AXL, endometrial cancer, uPA, MMP, ARK1 Received: May 12, 2016 Accepted: September 24, 2016 Published: October 13, 2016 ABSTRACT The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro , genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer.