1735P SARS-CoV-2 infection induces EMT-like molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer models
1735P SARS-CoV-2 infection induces EMT-like molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer models
复制标题
DOI：
10.1016/j.annonc.2020.08.1799
复制
发表时间：
2020-09-22
影响因子：
50.5
通讯作者：
Byers LA
中科院分区：
文献类型：
--
作者：
Stewart CA;Gay C;Ramkumar K;Cargill KR;Cardnell R;Nilsson M;Heeke S;Park EM;Kundu S;Diao L;Wang Q;Shen L;Xi Y;Della Corte CM;Kundu K;Gibbons DL;Wang J;Heymach JV;Byers LA
新冠肺炎是由SARS-CoV-2病毒引起的一种传染病，它通过细胞表面蛋白ACE2和TMPRSS2进入宿主细胞。利用多种正常和恶性模型及呼吸道组织，我们研究了ACE2和TMPRSS2的表达和调控。我们发现ACE2的表达仅限于一组高度上皮性的细胞。值得注意的是，SARS-CoV-2感染癌细胞系、支气管器官和患者鼻上皮，诱导与上皮向间充质转化(EMT)一致的代谢和转录变化，包括ZEB1和Ax1上调，导致EMT评分增加。此外，SARS-CoV-2感染会导致与紧密连接功能相关的基因转录缺失。SARS-CoV-2受体ACE2被EMT通过TGFbeta、ZEB1过表达和EGFR TKI抑制剂耐药而抑制。这提示了一种新的SARS-CoV-2致病模型，在该模型中，感染细胞向越来越多的间质状态转变，与具有急性呼吸窘迫综合征保护作用的紧密连接成分的丢失相关。AXL抑制和ZEB1减少，就像贝莫替尼一样，提供了一种潜在的逆转这种效应的策略。这些观察结果突出了空气消化，尤其是肺癌模型系统在探索SARS-CoV-2和其他呼吸道病毒的发病机制方面的效用，并为揭示新冠肺炎在健康患者和癌症患者中的发病率和死亡率的潜在机制提供了重要的见解。
COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of ZEB1 and AXL, resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike.