A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer

作者：Henrik Schinke, Enxian Shi, Zhongyang Lin, Tanja Quadt, Gisela Kranz, Jiefu Zhou, Hongxia Wang, Julia Heß, Steffen Heuer, Claus Belka, Horst Zitzelsberger, Udo Schumacher, Sandra Genduso, Kristoffer Riecken, Yujing Gao, Zhengquan Wu, Christoph A. Reichel, Christoph Walz, Martin Canis, Kristian Unger, Philipp Baumeister, Min Pan, Olivier Gires · 发表于：Molecular Cancer · 年份：2022 · DOI：10.1186/s12943-022-01646-1 · 被引用次数：85 · 研究领域：Head and Neck Cancer Studies、Cancer Cells and Metastasis、Ferroptosis and cancer prognosis

BACKGROUND: Epidermal growth factor receptor (EGFR) is both a driver oncogene and a therapeutic target in advanced head and neck squamous cell carcinoma (HNSCC). However, response to EGFR treatment is inconsistent and lacks markers for treatment prediction. This study investigated EGFR-induced epithelial-to-mesenchymal transition (EMT) as a central parameter in tumor progression and identified novel prognostic and therapeutic targets, and a candidate predictive marker for EGFR therapy response. METHODS: Transcriptomic profiles were analyzed by RNA sequencing (RNA-seq) following EGFR-mediated EMT in responsive human HNSCC cell lines. Exclusive genes were extracted via differentially expressed genes (DEGs) and a risk score was determined through forward feature selection and Cox regression models in HNSCC cohorts. Functional characterization of selected prognostic genes was conducted in 2D and 3D cellular models, and findings were validated by immunohistochemistry in primary HNSCC. RESULTS: An EGFR-mediated EMT gene signature composed of n = 171 genes was identified in responsive cell lines and transferred to the TCGA-HNSCC cohort. A 5-gene risk score comprising DDIT4, FADD, ITGB4, NCEH1, and TIMP1 prognosticated overall survival (OS) in TCGA and was confirmed in independent HNSCC cohorts. The EGFR-mediated EMT signature was distinct from EMT hallmark and partial EMT (pEMT) meta-programs with a differing enrichment pattern in single malignant cells. Molecular characterization s...