TY - JOUR
T1 - Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis
AU - Sinkevicius, Kerstin W.
AU - Kriegel, Christina
AU - Bellaria, Kelly J.
AU - Lee, Jaewon
AU - Lau, Allison N.
AU - Leeman, Kristen T.
AU - Zhou, Pengcheng
AU - Beede, Alexander M.
AU - Fillmore, Christine M.
AU - Caswell, Deborah
AU - Barrios, Juliana
AU - Wong, Kwok Kin
AU - Sholl, Lynette M.
AU - Schlaeger, Thorsten M.
AU - Bronson, Roderick T.
AU - Chirieac, Lucian R.
AU - Winslow, Monte M.
AU - Haigis, Marcia C.
AU - Kim, Carla F.
PY - 2014/7/15
Y1 - 2014/7/15
N2 - 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.
AB - 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.
KW - NSCLC
KW - TrkB/NTRK2
UR - http://www.scopus.com/inward/record.url?scp=84904368562&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904368562&partnerID=8YFLogxK
U2 - 10.1073/pnas.1404399111
DO - 10.1073/pnas.1404399111
M3 - Article
C2 - 24982195
AN - SCOPUS:84904368562
SN - 0027-8424
VL - 111
SP - 10299
EP - 10304
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -