Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis

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 throu...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-07, Vol.111 (28), p.10299-10304
Main Authors: Sinkevicius, Kerstin W., Kriegel, Christina, Bellaria, Kelly J., Lee, Jaewon, Lau, Allison N., Leeman, Kristen T., Zhou, Pengcheng, Beede, Alexander M., Fillmore, Christine M., Caswell, Deborah, Barrios, Juliana, Wong, Kwok-Kin, Sholl, Lynette M., Schlaeger, Thorsten M., Bronson, Roderick T., Chirieac, Lucian R., Winslow, Monte M., Haigis, Marcia C., Kim, Carla F.
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - drug therapy
Adenocarcinoma - enzymology
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Animals
Biological Sciences
Brain
Cell adhesion & migration
Cell Line, Tumor
Cell lines
Cell Movement
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Hypoxia
Hypoxia-Inducible Factor 1 - genetics
Hypoxia-Inducible Factor 1 - metabolism
Lung cancer
Lung neoplasms
Lung Neoplasms - drug therapy
Lung Neoplasms - enzymology
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Lung Neoplasms - secondary
Lungs
Lymph nodes
Membrane Glycoproteins - biosynthesis
Membrane Glycoproteins - genetics
Metastasis
Mice
Mice, Mutant Strains
Mutation
Neoplasm Metastasis - genetics
Neoplasm Metastasis - pathology
Protein-Tyrosine Kinases - biosynthesis
Protein-Tyrosine Kinases - genetics
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Receptor, trkB - biosynthesis
Receptor, trkB - genetics
Signal Transduction - genetics
Tumor cell line
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1404399111