ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway

Chen Yuan Lin, Hung Jen Chen, Cheng Chung Huang, Liang Chuan Lai, Tzu Pin Lu, Guan Chin Tseng, Ting Ting Kuo, Qian Yu Kuok, Jennifer L. Hsu, Shian Ying Sung, Mien Chie Hung, Yuh Pyng Sher

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36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5229-5243
Number of pages15
JournalCancer Research
Volume74
Issue number18
DOIs
Publication statusPublished - Jul 24 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Lin, C. Y., Chen, H. J., Huang, C. C., Lai, L. C., Lu, T. P., Tseng, G. C., Kuo, T. T., Kuok, Q. Y., Hsu, J. L., Sung, S. Y., Hung, M. C., & Sher, Y. P. (2014). ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway. Cancer Research, 74(18), 5229-5243. https://doi.org/10.1158/0008-5472.CAN-13-2995