Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis

Kerstin W. Sinkevicius, Christina Kriegel, Kelly J. Bellaria, Jaewon Lee, Allison N. Lau, Kristen T. Leeman, Pengcheng Zhou, Alexander M. Beede, Christine M. Fillmore, Deborah Caswell, Juliana Barrios, Kwok Kin Wong, Lynette M. Sholl, Thorsten M. Schlaeger, Roderick T. Bronson, Lucian R. Chirieac, Monte M. Winslow, Marcia C. Haigis, Carla F. Kim

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxia-inducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma.

Original languageEnglish
Pages (from-to)10299-10304
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number28
DOIs
StatePublished - Jul 15 2014

Keywords

  • NSCLC
  • TrkB/NTRK2

ASJC Scopus subject areas

  • General

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