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

Cancers

Corinna Kronenthaler¹  Elena Weigl¹  Gudrun Dandekar¹  Jesús Guillermo Nieves Pereira¹  Anna Schliermann¹  Claudia Göttlich¹  Sarah Nietzer¹  Matthias Peindl¹  Celina May¹  Tamara Lüttgens¹  Franziska Schmitt¹  Niklas Hoff¹  Julia Schüler²  Samantha Crouch³  Thomas Dandekar³  Andreas Rosenwald⁴  Simone Reu-Hofer⁴  Danjouma Cheufou⁵  Thorsten Walles⁶ 

[1] Chair of Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Röntgenring 11, 97070 Würzburg, Germany;Charles River Discovery Research Services Germany GmbH, Am Flughafen, 14, 79108 Freiburg, Germany;Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany;Department of Pathology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany;Department of Thoracic Surgery, Klinikum Würzburg Mitte gGmbH, Salvatorstr. 7, 97074 Würzburg, Germany;Department of Thoracic Surgery, University Medicine Magdeburg, Leipziger Straße 44, 39120 Magdeburg, Germany;

关键词: EMT;    drug resistance;    invasion;    stemness;    3D lung tumor tissue models;    KRAS biomarker signatures;   

DOI  :  10.3390/cancers14092176

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown