title: ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway.
abstract: The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease.
authors: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. Division of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan.
authors: Chen-Yuan
authors: CY
authors: Lin
authors: Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
authors: Hung-Jen
authors: HJ
authors: Chen
authors: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors: Cheng-Chung
authors: CC
authors: Huang
authors: Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan.
authors: Liang-Chuan
authors: LC
authors: Lai
authors: YongLin Biomedical Engineering Center, National Taiwan University, Taipei, Taiwan.
authors: Tzu-Pin
authors: TP
authors: Lu
authors: Department of Pathology, China Medical University Hospital, Taichung, Taiwan.
authors: Guan-Chin
authors: GC
authors: Tseng
authors: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors: Ting-Ting
authors: TT
authors: Kuo
authors: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors: Qian-Yu
authors: QY
authors: Kuok
authors: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biotechnology, Asia University, Taichung, Taiwan.
authors: Jennifer L
authors: JL
authors: Hsu
authors: PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors: Shian-Ying
authors: SY
authors: Sung
authors: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biotechnology, Asia University, Taichung, Taiwan. Graduate Institute for Cancer Biology, China Medical University, Taichung, Taiwan. mhung@mdanderson.org ypsher@mail.cmu.edu.tw.
authors: Mien-Chie
authors: MC
authors: Hung
authors: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. mhung@mdanderson.org ypsher@mail.cmu.edu.tw.
authors: Yuh-Pyng
authors: YP
authors: Sher
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D000069439:Dasatinib; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011743:Pyrimidines; D013844:Thiazoles; D003907:Dexamethasone; D010960:Plasminogen Activators; D051722:ADAM Proteins; C098339:ADAM9 protein, human; D000069439:Dasatinib