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Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10299-304. doi: 10.1073/pnas.1404399111. Epub 2014 Jun 30.

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

Author information

1
Stem Cell Program, Boston Children's Hospital, Boston MA 02115;Harvard Stem Cell Institute, Cambridge, MA 02138;Department of Genetics, Harvard Medical School, Boston, MA 02115;
2
Department of Cell Biology and The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115;
3
Department of Pediatrics, Division of Newborn Medicine, Boston Children's Hospital Boston, Harvard Medical School, Boston, MA 02115;
4
Department of Pediatric Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115;Department of Neurobiology, Harvard Medical School, Boston, MA 02115;
5
Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305;
6
Department of Medical Oncology and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115;Department of Medicine, Harvard Medical School, Boston, MA 02115;
7
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
8
Stem Cell Program, Boston Children's Hospital, Boston MA 02115;Harvard Stem Cell Institute, Cambridge, MA 02138;
9
Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115; and.
10
Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305;Department of Genetics and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
11
Stem Cell Program, Boston Children's Hospital, Boston MA 02115;Harvard Stem Cell Institute, Cambridge, MA 02138;Department of Genetics, Harvard Medical School, Boston, MA 02115; carla.kim@childrens.harvard.edu.

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.

KEYWORDS:

NSCLC; TrkB/NTRK2

PMID:
24982195
PMCID:
PMC4104911
DOI:
10.1073/pnas.1404399111
[Indexed for MEDLINE]
Free PMC Article

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