EGFR 诱导的上皮间质转化的转录组图谱确定了头颈部癌症的预后和治疗靶点。
A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer.
机构信息
Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University, Munich, Marchioninistr. 15, 81377, Munich, Germany.
State Key Laboratory of Oncogenes and Related Genes, Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, China.
出版信息
Mol Cancer. 2022 Sep 8;21(1):178. doi: 10.1186/s12943-022-01646-1.
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 showed that ITGB4 was upregulated in primary tumors and metastases compared to normal mucosa and correlated with EGFR/MAPK activity in tumor bulk and single malignant cells. Preferential localization of ITGB4 together with its ligand laminin 5 at tumor-stroma interfaces correlated with increased tumor budding in primary HNSCC tissue sections. In vitro, ITGB4 knock-down reduced EGFR-mediated migration and invasion and ITGB4-antagonizing antibody ASC8 impaired 2D and 3D invasion. Furthermore, a logistic regression model defined ITGB4 as a predictive marker of progression-free survival in response to Cetuximab in recurrent metastatic HNSCC patients.
CONCLUSIONS
EGFR-mediated EMT conveyed through MAPK activation contributes to HNSCC progression upon induction of migration and invasion. A 5-gene risk score based on a novel EGFR-mediated EMT signature prognosticated survival of HNSCC patients and determined ITGB4 as potential therapeutic and predictive target in patients with strong EGFR-mediated EMT.
背景
表皮生长因子受体（EGFR）既是驱动癌基因，也是晚期头颈部鳞状细胞癌（HNSCC）的治疗靶点。然而，对 EGFR 治疗的反应不一致，缺乏治疗预测标志物。本研究调查了 EGFR 诱导的上皮-间充质转化（EMT）作为肿瘤进展的中心参数，并确定了新的预后和治疗靶点，以及 EGFR 治疗反应的候选预测标志物。
方法
通过 RNA 测序（RNA-seq）分析 EGFR 介导的反应性人 HNSCC 细胞系中的 EMT 后的转录组谱。通过差异表达基因（DEGs）提取特有基因，并通过正向特征选择和 Cox 回归模型在 HNSCC 队列中确定风险评分。在 2D 和 3D 细胞模型中对选定的预后基因进行功能表征，并通过原发性 HNSCC 的免疫组织化学验证。
结果
在反应性细胞系中鉴定了由 n = 171 个基因组成的 EGFR 介导的 EMT 基因特征，并将其转移到 TCGA-HNSCC 队列中。由 DDIT4、FADD、ITGB4、NCEH1 和 TIMP1 组成的 5 个基因风险评分可预测 TCGA 中的总生存期（OS），并在独立的 HNSCC 队列中得到证实。EGFR 介导的 EMT 特征与 EMT 标志和部分 EMT（pEMT）元程序不同，在单个恶性细胞中具有不同的富集模式。分子特征表明，与正常粘膜相比，ITGB4 在原发性肿瘤和转移瘤中上调，并与肿瘤块和单个恶性细胞中的 EGFR/MAPK 活性相关。在原发性 HNSCC 组织切片中，ITGB4 及其配体层粘连蛋白 5 优先定位于肿瘤-基质界面，与肿瘤芽生增加相关。在体外，ITGB4 敲低减少了 EGFR 介导的迁移和侵袭，而 ITGB4 拮抗抗体 ASC8 则削弱了 2D 和 3D 侵袭。此外，逻辑回归模型将 ITGB4 定义为复发性转移性 HNSCC 患者对 Cetuximab 无进展生存期的预测标志物。
结论
通过 MAPK 激活传递的 EGFR 介导的 EMT 促进了诱导迁移和侵袭后的 HNSCC 进展。基于新型 EGFR 介导的 EMT 特征的 5 个基因风险评分可预测 HNSCC 患者的生存，并确定 ITGB4 作为具有强烈 EGFR 介导的 EMT 的患者的潜在治疗和预测靶点。
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