Host JDP2 expression in the bone marrow contributes to metastatic spread

// Yelena Barbarov 1 , Michael Timaner 1 , Dror Alishekevitz 1 , Tsonwin Hai 2 , Kazunari K. Yokoyama 3 , Yuval Shaked 1, * , Ami Aronheim 1, * 1 Department of Cell Biology and Cancer Science, the B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 2 Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, Ohio, USA 3 Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan * These authors have contributed equally to this work Correspondence to: Ami Aronheim, e-mail: aronheim@tx.technion.ac.il Yuval Shaked, e-mail: yshaked@tx.technion.ac.il Keywords: JDP2, metastasis, CCL5, bone marrow derived cells, lewis lung carcinoma Received: June 29, 2015      Accepted: October 02, 2015      Published: October 14, 2015 ABSTRACT The c-Jun Dimerization Protein 2, JDP2, is a basic leucine zipper protein member of the activator protein-1 (AP-1) family of transcription factors. JDP2 typically suppresses gene transcription through multiple mechanisms and plays a dual role in multiple cellular processes, including cell differentiation and proliferation which is dependent on AP-1 function. Whereas the role of JDP2 expression within cancer cells has been studied, its role in stromal cells at the tumor microenvironment is largely unknown. Here we show that mice lacking JDP2 (JDP2−/−) display a reduced rate of metastasis in Lewis lung carcinoma (LLC) and polyoma middle T-antigen (PyMT) breast carcinoma mouse models. The replacement of wild-type bone marrow derived cells (BMDCs) with JDP2-deficient BMDCs recapitulates the metastatic phenotype of JDP2−/− tumor-bearing mice. In vitro , conditioned medium of wild-type BMDCs significantly potentiates the migration and invasion capacity of LLC cells as compared to that of JDP2−/− BMDCs. Furthermore, wild-type BMDCs secrete CCL5, a chemokine known to contribute to metastasis, to a greater extent than JDP2−/− BMDCs. The supplementation of CCL5 in JDP2−/− BMDC conditioned medium was sufficient to potentiate the invasion capacity of LLC. Overall, this study suggests that JDP2-expressing BMDCs within the tumor microenvironment contribute to metastatic spread.