TY  - JOUR
A1  - Götz, Rudolf
A1  - Sendtner, Michael
T1  - Cooperation of Tyrosine Kinase Receptor TrkB and Epidermal Growth Factor Receptor Signaling Enhances Migration and Dispersal of Lung Tumor Cells
JF  - PLoS ONE
N2  - TrkB mediates the effects of brain-derived neurotrophic factor (BDNF) in neuronal and nonnneuronal cells. Based on recent reports that TrkB can also be transactivated through epidermal growth-factor receptor (EGFR) signaling and thus regulates migration of early neurons, we investigated the role of TrkB in migration of lung tumor cells. Early metastasis remains a major challenge in the clinical management of non-small cell lung cancer (NSCLC). TrkB receptor signaling is associated with metastasis and poor patient prognosis in NSCLC. Expression of this receptor in A549 cells and in another adenocarcinoma cell line, NCI-H441, promoted enhanced migratory capacity in wound healing assays in the presence of the TrkB ligand BDNF. Furthermore, TrkB expression in A549 cells potentiated the stimulatory effect of EGF in wound healing and in Boyden chamber migration experiments. Consistent with a potential loss of cell polarity upon TrkB expression, cell dispersal and de-clustering was induced in A549 cells independently of exogeneous BDNF. Morphological transformation involved extensive cytoskeletal changes, reduced E-cadherin expression and suppression of E-cadherin expression on the cell surface in TrkB expressing tumor cells. This function depended on MEK and Akt kinase activity but was independent of Src. These data indicate that TrkB expression in lung adenoma cells is an early step in tumor cell dissemination, and thus could represent a target for therapy development.
KW  - metastasis
KW  - neurons
KW  - non-small cell lung cancer
KW  - neuron migration
KW  - adenocarcinoma of the lung
KW  - vector cloning
KW  - lung and intrathoracic tumors
KW  - secondary lung tumors
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119578
SN  - 1932-6203
VL  - 9
IS  - 6
ER  - 
TY  - JOUR
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Maier, Carina R.
A1  - Fischer, Thomas
A1  - Prieto-Garcia, Cristian
A1  - Baluapuri, Apoorva
A1  - Schwarz, Jessica
A1  - Schmitz, Werner
A1  - Garrido-Rodriguez, Martin
A1  - Pahor, Nikolett
A1  - Davies, Clare C.
A1  - Bassermann, Florian
A1  - Orian, Amir
A1  - Wolf, Elmar
A1  - Schulze, Almut
A1  - Calzado, Marco A.
A1  - Rosenfeldt, Mathias T.
A1  - Diefenbacher, Markus E.
T1  - Implementation of CRISPR/Cas9 Genome Editing to Generate Murine Lung Cancer Models That Depict the Mutational Landscape of Human Disease
JF  - Frontiers in Cell and Developmental Biology
N2  - Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.
KW  - non-small cell lung cancer
KW  - CRISPR-Cas9
KW  - mouse model
KW  - lung cancer
KW  - MYC
KW  - JUN
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230949
SN  - 2296-634X
VL  - 9
ER  -