Dataset Information

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

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.

SUBMITTER: Sinkevicius KW

PROVIDER: S-EPMC4104911 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

Sinkevicius Kerstin W KW Kriegel Christina C Bellaria Kelly J KJ Lee Jaewon J Lau Allison N AN Leeman Kristen T KT Zhou Pengcheng P Beede Alexander M AM Fillmore Christine M CM Caswell Deborah D Barrios Juliana J Wong Kwok-Kin KK Sholl Lynette M LM Schlaeger Thorsten M TM Bronson Roderick T RT Chirieac Lucian R LR Winslow Monte M MM Haigis Marcia C MC Kim Carla F CF

Proceedings of the National Academy of Sciences of the United States of America 20140630 28

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 i ...[more]

PMID: 24982195

Similar Datasets

Project description:BackgroundThe NTRK2 genetic locus encodes neurotrophin membrane receptors that play an important role in normal neural tissue plasticity, growth, and survival. One NTRK2-encoded protein is TrkB-FL, which can regulate multiple pathways relevant to cancer. A second NTRK2 gene mRNA isoform encodes TrkB-T1, a receptor that has a different cytoplasmic domain encoded in a mRNA with a unique 3' terminal exon.MethodTumors from The Cancer Genome Atlas (TCGA) and other studies were classified according to the expression of a single form of NTRK2 mRNA, TrkB-T1, identified by its unique 3' terminal exon. Analysis of differentially expressed genes in TrkB-T1 high expressers was done to determine if tumors enriched for TrkB-T1 mRNA were a uniform group independent of anatomic site.ResultsThe mRNA for TrkB-T1 is the most abundant NTRK2 gene mRNA in all squamous cell carcinomas (SCCs) in the TCGA database. Comparison of larynx SCC high TrkB-T1 RNA expressers to low expressers (n = 96) revealed gene expression differences consistent with the high TrkB-T1 tumors being more neural-like. The upregulated genes in the TrkB-T1 RNA high expressers also showed enrichment of pathways involved in retinol metabolism, hedgehog signaling, and the Nfe2l2 response, among other pathways. An examination of oral, esophagus, and lung SCCs (n = 284, 97, 501) showed induction of the same pathways among tumors that expressed high levels of TrkB-T1 mRNA. Proteins associated with regulation of the sonic hedgehog pathway, and the Nfe2l2 response, Tp63, and Keap1 and p62/SQSTM1 proteins, showed differential expression in larynx, oral and lung high TrkB1-T1 expresser SCCs. Unexpectantly, the relationship of high level TrkB-T1 expression to patient outcomes was SCC anatomic site specific. High TrkB-T1 mRNA levels in laryngeal SCC correlated with poor survival, but the opposite was true for lung SCC. This may be because pathways enriched in the TrkB high expressers, like those involving oncogenes NFE2L2, PIK3CA, and SOX2, are known to have SCC anatomic site-specific effects on progression.ConclusionsHigh level TrkB-T1 mRNA is a marker of a distinct SCC subtype enriched for at least 3 pathways relevant to tumor progression: Nfe2l2 response, retinol metabolism, and hedgehog signaling.

Dataset Information

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

Publications

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets