NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM

Osborne, Jihan K.; Larsen, Jill E.; Shields, Morgan C.; Gonzales, Joshua X.; Shames, David S.; Sato, Mitsuo; Kulkarni, Ashwinikumar; Wistuba, Ignacio I.; Girard, Luc; Minna, John D.; Cobb, Melanie H.

doi:10.1073/pnas.1303932110

Cited by 84 publications

(89 citation statements)

References 47 publications

(57 reference statements)

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“…However, TrkB is a candidate receptor for regulation of the PDK1-Akt axis during neuronal migration, because TrkB is localized along the leading process of migrating interneurons derived from the medial ganglionic eminence, TrkB stimulation by BDNF activates Akt in cortical neurons, and cortical neuronal migration is delayed by knockdown or knockout of TrkB or by knockin mutation of TrkB intracellular residues critical for Akt activation (39,43,44). The proneural transcription factor NeuroD1 was recently shown to up-regulate TrkB expression (45), suggesting that cortical cells may gain responsiveness to TrkB ligands (such as BDNF) on commitment to the neuronal fate. In addition, the extracellular matrix component laminin γ1 and its integrin receptor might function upstream of the PDK1-Akt pathway during neuronal migration (46).…”

Section: Gsk3βmentioning

confidence: 99%

PDK1–Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex

Itoh

Higuchi

Oishi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Neurons migrate a long radial distance by a process known as locomotion in the developing mammalian neocortex. During locomotion, immature neurons undergo saltatory movement along radial glia fibers. The molecular mechanisms that regulate the speed of locomotion are largely unknown. We now show that the serine/threonine kinase Akt and its activator phosphoinositide-dependent protein kinase 1 (PDK1) regulate the speed of locomotion of mouse neocortical neurons through the cortical plate. Inactivation of the PDK1–Akt pathway impaired the coordinated movement of the nucleus and centrosome, a microtubule-dependent process, during neuronal migration. Moreover, the PDK1–Akt pathway was found to control microtubules, likely by regulating the binding of accessory proteins including the dynactin subunit p150glued. Consistent with this notion, we found that PDK1 regulates the expression of cytoplasmic dynein intermediate chain and light intermediate chain at a posttranscriptional level in the developing neocortex. Our results thus reveal an essential role for the PDK1–Akt pathway in the regulation of a key step of neuronal migration.

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Section: Gsk3βmentioning

confidence: 99%

PDK1–Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex

Itoh

Higuchi

Oishi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Transient knockdown of TrkB in the lung adenocarcinoma cell line A549 inhibited cell invasion in culture (27), and treatment of A549 cells with the pan-Trk inhibitor K252a induced cell death and reduced the ability of the cells to form colonies in soft agar (28). Reduction of TrkB signaling similarly decreased invasion, soft agar colony formation, and tumor xenograft growth of small-cell lung cancer neuroendocrine cell lines (29). TrkB was originally identified as a supressor of anoikis (6), yet TrkB knockdown did not alter anoikis in our studies (Fig.…”

Section: Discussionmentioning

confidence: 98%

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis

Sinkevicius

Kriegel

Bellaria

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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 tropomyosinrelated 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. Hypoxiainducible 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.TrkB/NTRK2 | NSCLC L ung cancer remains the major cause of death from cancer worldwide. The two types of lung cancer are non-small-cell lung cancers (NSCLCs; 80% of all lung cancers), which include adenocarcinomas, squamous cell carcinomas, and large cell carcinomas, and small-cell lung cancers (20%, exhibiting neuroendocrine features). The average 5-y survival rate for NSCLC is only 16% (1). Most NSCLC patients have advanced disease at diagnosis; 22% have regional lymph node metastases, and 56% have distant metastases in the brain, bone, liver, or adrenal glands (1). Surgery or therapies that treat primary lung tumors rarely prevent metastases (1). Understanding the mechanisms of NSCLC metastasis is crucial for the development of new therapies to improve survival for lung cancer patients.Tropomyosin-related kinase B (TrkB; also called NTRK2), a neurotrophin receptor, is important for neural development and is an independent prognostic marker in many tumor types (2). TrkB-expressing neural precursors migrate from their proliferative zone toward a gradient of the TrkB ligand, brainderived neurotrophic factor (BDNF), which is made near the site of residence of the mature neurons (3). High levels of TrkB are correlated with poor patient prognosis in neuroblastomas and ovarian, pancreatic, colon, prostate, and gastric cancers (2). TrkB was overexpressed in ovarian adenocarcinoma metastases compared with primary lesions (4). TrkB is also a supressor of anoikis in cell lines (5). Finally, overexpression of TrkB and BDNF in nonmalignant rat intestinal epithelial cells promoted metastasis from s.c. injection sites to the lungs (6).Despite these clues that TrkB regulates parts of the metastatic cascade in other tumor types, the role of TrkB in NSCLC metastasis remains unclear. TrkB immunoreactivity was correlated with advanced stage disease in lung squamous cell carcinomas, yet was also correlated with better survival (7). In contrast, TrkB expression was as...

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“…siRNA reverse transfections were performed as described previously (52), and cells were harvested 48 hours after transfection for in vitro tumorigenicity assays. siRNA, proliferation, anchoragedependent, and -independent (soft agar) colony formation, migration (scratch), Matrigel invasion, and ChIP assays were performed as previously described (3,4,53), with additional details provided in Supplemental Methods. FACS was performed as previously described (33) using dual staining for CD24 and CD44 (Supplemental Table 8) with propidium iodide exclusion of nonviable cells.…”

Section: Methodsmentioning

confidence: 99%

“…Subcutaneous and intravenous xenograft growth were evaluated as previously described in female NOD/SCID mice (4,53).…”

Section: Methodsmentioning

confidence: 99%