TY  - JOUR
A1  - Fecher, David
A1  - Hofmann, Elisabeth
A1  - Buck, Andreas
A1  - Bundschuh, Ralph
A1  - Nietzer, Sarah
A1  - Dandekar, Gudrun
A1  - Walles, Thorsten
A1  - Walles, Heike
A1  - Lückerath, Katharina
A1  - Steinke, Maria
T1  - Human Organotypic Lung Tumor Models: Suitable For Preclinical \(^{18}\)F-FDG PET-Imaging
JF  - PLoS ONE
N2  - Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[\(^{18}\)F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future.
KW  - lung and intrathoracic tumors
KW  - trachea
KW  - adenocarcinoma of the lung
KW  - cancer treatment
KW  - secondary lung tumors
KW  - pulmonary imaging
KW  - extracellular matrix
KW  - collagens
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179678
VL  - 11
IS  - 8
ER  - 
TY  - JOUR
A1  - Peindl, Matthias
A1  - Göttlich, Claudia
A1  - Crouch, Samantha
A1  - Hoff, Niklas
A1  - Lüttgens, Tamara
A1  - Schmitt, Franziska
A1  - Pereira, Jesús Guillermo Nieves
A1  - May, Celina
A1  - Schliermann, Anna
A1  - Kronenthaler, Corinna
A1  - Cheufou, Danjouma
A1  - Reu-Hofer, Simone
A1  - Rosenwald, Andreas
A1  - Weigl, Elena
A1  - Walles, Thorsten
A1  - Schüler, Julia
A1  - Dandekar, Thomas
A1  - Nietzer, Sarah
A1  - Dandekar, Gudrun
T1  - EMT, stemness, and drug resistance in biological context: a 3D tumor tissue/in silico platform for analysis of combinatorial treatment in NSCLC with aggressive KRAS-biomarker signatures
JF  - Cancers
N2  - Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.
KW  - EMT
KW  - drug resistance
KW  - invasion
KW  - stemness
KW  - 3D lung tumor tissue models
KW  - KRAS biomarker signatures
KW  - boolean in silico models
KW  - targeted combination therapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270744
SN  - 2072-6694
VL  - 14
IS  - 9
ER  -