Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors

// Tomer Meirson 1, 2, * , Alessandro Genna 1, * , Nikola Lukic 1 , Tetiana Makhnii 1 , Joel Alter 1 , Ved P. Sharma 3, 4, 5 , Yarong Wang 3, 4, 5 , Abraham O. Samson 2 , John S. Condeelis 3, 4, 5 and Hava Gil-Henn 1 1 Laboratory of Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel 2 Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel 3 Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA 4 Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA 5 Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, New York 10461, USA * These authors contributed equally to this work Correspondence to: Hava Gil-Henn, email: Hava.Henn@biu.ac.il Keywords: ABL kinases; inhibitors; invadopodia; in vivo; cancer metastasis Received: November 06, 2017      Accepted: April 08, 2018      Published: April 24, 2018 ABSTRACT Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in breast cancer patients. While researchers have identified treatments that shrink or slow metastatic tumors, no treatment that permanently eradicates metastasis exists at present. Here, we show that the ABL kinase inhibitors imatinib, nilotinib, and GNF-5 impede invadopodium precursor formation and cortactin-phosphorylation dependent invadopodium maturation, leading to decreased actin polymerization in invadopodia, reduced extracellular matrix degradation, and impaired matrix proteolysis-dependent invasion. Using a mouse xenograft model we demonstrate that, while primary tumor size is not affected by ABL kinase inhibitors, the in vivo matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs are significantly impaired in inhibitor-treated mice. Further proteogenomic analysis of breast cancer patient databases revealed co-expression of the Abl-related gene (Arg) and cortactin across all hormone- and human epidermal growth factor receptor 2 (HER2)-receptor status tumors, which correlates synergistically with distant metastasis and poor patient prognosis. Our findings establish a prognostic value for Arg and cortactin as predictors of metastatic dissemination and suggest that therapeutic inhibition of ABL kinases may be used for blocking breast cancer metastasis.