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  - 
TY  - JOUR
A1  - Habenstein, Jens
A1  - Schmitt, Franziska
A1  - Liessem, Sander
A1  - Ly, Alice
A1  - Trede, Dennis
A1  - Wegener, Christian
A1  - Predel, Reinhard
A1  - Rössler, Wolfgang
A1  - Neupert, Susanne
T1  - Transcriptomic, peptidomic, and mass spectrometry imaging analysis of the brain in the ant Cataglyphis nodus
JF  - Journal of Neurochemistry
N2  - Behavioral flexibility is an important cornerstone for the ecological success of animals. Social Cataglyphis nodus ants with their age‐related polyethism characterized by age‐related behavioral phenotypes represent a prime example for behavioral flexibility. We propose neuropeptides as powerful candidates for the flexible modulation of age‐related behavioral transitions in individual ants. As the neuropeptidome of C. nodus was unknown, we collected a comprehensive peptidomic data set obtained by transcriptome analysis of the ants’ central nervous system combined with brain extract analysis by Q‐Exactive Orbitrap mass spectrometry (MS) and direct tissue profiling of different regions of the brain by matrix‐assisted laser desorption/ionization time‐of‐flight (MALDI‐TOF) MS. In total, we identified 71 peptides with likely bioactive function, encoded on 49 neuropeptide‐, neuropeptide‐like, and protein hormone prepropeptide genes, including a novel neuropeptide‐like gene (fliktin). We next characterized the spatial distribution of a subset of peptides encoded on 16 precursor proteins with high resolution by MALDI MS imaging (MALDI MSI) on 14 µm brain sections. The accuracy of our MSI data were confirmed by matching the immunostaining patterns for tachykinins with MSI ion images from consecutive brain sections. Our data provide a solid framework for future research into spatially resolved qualitative and quantitative peptidomic changes associated with stage‐specific behavioral transitions and the functional role of neuropeptides in Cataglyphis ants.
KW  - brain
KW  - MALDI imaging
KW  - neuropeptides
KW  - neuropeptidomics
KW  - social insect
KW  - transcriptomics
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239917
VL  - 158
IS  - 2
SP  - 391
EP  - 412
ER  -