Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University, Munich, Germany.
Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
PLoS Biol. 2018 Sep 27;16(9):e2006624. doi: 10.1371/journal.pbio.2006624. eCollection 2018 Sep.
Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhigh HNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs.
头颈部鳞状细胞癌 (HNSCC) 的特征是具有显著的分子异质性，导致严重的治疗耐药和临床预后不良。上皮-间充质转化 (EMT) 的间质和肿瘤内异质性最近被揭示为临床预后不良的主要参数。在这里，我们研究了治疗靶点表皮生长因子受体 (EGFR) 和上皮分化的主要决定因素上皮细胞黏附分子 (EpCAM) 在 HNSCC 的临床样本和体外模型中的表达和功能。我们描述了 EGFRlow/EpCAMhigh HNSCC 患者（n = 180）的生存率提高，并为观察到的临床结果差异提供了分子基础。EGF/EGFR 通过差异激活中央分子开关磷酸化细胞外信号调节激酶 1/2(pERK1/2) 和 EMT 转录因子 (EMT-TFs) Snail、锌指 E 盒结合同源框 1(Zeb1) 和 Slug，具有浓度依赖性的双重增殖和 EMT 诱导能力。此外，EpCAM 的可溶性外显子 (EpEX) 被鉴定为 EGFR 的配体，可激活 pERK1/2 和磷酸化 AKT(pAKT)，并诱导 EGFR 依赖性增殖，但抑制 EGF 介导的 EMT、Snail、Zeb1 和 Slug 激活和细胞迁移。EpEX 通过竞争性调节 pERK1/2 激活强度和抑制 EMT-TFs 来实现 EMT 的抑制，这在临床样本中的 pERK1/2 和其靶标 Slug 的水平上得到反映。因此，pERK1/2 和/或 Slug 的高表达预测了 HNSCC 的不良预后。因此，EpEX 是 EGFR 的配体，可诱导增殖，但可拮抗 EGF/EGFR/pERK1/2 轴介导的 EMT。因此，新兴的 EGFR/EpCAM 分子相互作用代表了改善 HNSCC 患者个体化辅助治疗的有希望的靶点。
