Höpfl Sebastian, Özverin Merih, Nowack Helena, Tamas Raluca, Clark Andrew G, Radde Nicole, Olayioye Monilola A
Institute for Stochastics and Applications, University of Stuttgart, Stuttgart, Germany.
Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany.
PLoS Comput Biol. 2025 May 12;21(5):e1013076. doi: 10.1371/journal.pcbi.1013076. eCollection 2025 May.
Epithelial-mesenchymal transition (EMT) plays an essential role in embryonic development, wound healing, and tumor progression. Partial EMT states have been linked to metastatic dissemination and drug resistance. Several interconnected feedback loops at the RNA and protein levels control the transition between different cellular states. Using a combination of mathematical modeling and experimental analyses in the TGFβ-responsive breast epithelial MCF10A cell model, we identify a central role for the tumor suppressor protein Deleted in Liver Cancer 1 (DLC1) during EMT. By extending a previous model of EMT comprising key transcription factors and microRNAs, our work shows that DLC1 acts as a positive regulator of TGFβ-driven EMT, mainly by promoting SNAIL1 expression. Our model predictions indicate that DLC1 loss impairs EMT progression. Experimental analyses confirm this prediction and reveal the acquisition of a partial EMT phenotype in DLC1-depleted cells. Furthermore, our model results indicate a possible EMT reversion to partial or epithelial states upon DLC1 loss in MCF10A cells induced toward mesenchymal phenotypes. The increased EMT plasticity of cells lacking DLC1 may explain its importance as a tumor suppressor.
上皮-间质转化（EMT）在胚胎发育、伤口愈合和肿瘤进展中起着至关重要的作用。部分EMT状态与转移扩散和耐药性有关。RNA和蛋白质水平上的几个相互关联的反馈环控制着不同细胞状态之间的转变。通过在TGFβ反应性乳腺上皮MCF10A细胞模型中结合数学建模和实验分析，我们确定了肿瘤抑制蛋白肝癌缺失1（DLC1）在EMT过程中的核心作用。通过扩展先前包含关键转录因子和微小RNA的EMT模型，我们的研究表明DLC1主要通过促进SNAIL1表达，作为TGFβ驱动的EMT的正向调节因子。我们的模型预测表明DLC1缺失会损害EMT进程。实验分析证实了这一预测，并揭示了DLC1缺失细胞中部分EMT表型的获得。此外，我们的模型结果表明，在诱导向间充质表型的MCF10A细胞中，DLC1缺失后EMT可能会逆转至部分或上皮状态。缺乏DLC1的细胞增加的EMT可塑性可能解释了其作为肿瘤抑制因子的重要性。
