Peindl Matthias, Göttlich Claudia, Crouch Samantha, Hoff Niklas, Lüttgens Tamara, Schmitt Franziska, Pereira Jesús Guillermo Nieves, May Celina, Schliermann Anna, Kronenthaler Corinna, Cheufou Danjouma, Reu-Hofer Simone, Rosenwald Andreas, Weigl Elena, Walles Thorsten, Schüler Julia, Dandekar Thomas, Nietzer Sarah, Dandekar Gudrun
Chair of Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Cancers (Basel). 2022 Apr 27;14(9):2176. doi: 10.3390/cancers14092176.
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 or mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in -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 inhibitor in mutant HCC44 models, which, besides EMT, display mutations in , , 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.
上皮-间质转化（EMT）被认为在侵袭、干性和耐药性中起核心作用。评估这一过程生物学复杂性的实验模型有限。为了更深入了解EMT的影响并更可靠地测试药物反应，我们使用了一种基于去细胞化肠基质的肺癌测试系统，该系统显示出更接近体内的增殖水平以及临床标志物和致癌相关基因的表达增强。在我们的模型中，我们发现了在携带或突变的原发性和继发性耐药细胞中EMT与耐药性之间存在相关性的证据，这是基于优化的信号网络拓扑结构在计算机上模拟得出的。值得注意的是，在突变的患者来源异种移植（PDX）细胞系中，耐药性与EMT状态无关，并且通过TGF-β诱导EMT并不影响药物疗效。为了进一步研究药物反应的其他决定因素，我们在突变的HCC44模型中测试了几种药物与KRAS抑制剂的联合使用，该模型除了EMT外，还在、和中显示突变且c-MYC表达较高。我们确定极光激酶A（AURKA）抑制剂是最有前景的候选药物。在我们的网络中，AURKA是与EMT、增殖、凋亡、LKB1和c-MYC中心相连的枢纽。这例证了我们用于生物标志物特征临床转化的系统分析方法。
