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

Abstract

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.

A ferroptosis-related prognostic model with excellent clinical performance based on the exploration of the mechanism of oral squamous cell carcinoma progression

“…DDIT4 (also known as REDD1) regulates p53/TP53 mediator apoptosis in response to DNA damage and regulates cell growth, proliferation and survival by inhibiting the activity of mammalian target of rapamycin complex 1 (mTORC1) [35][36][37] . Previous literature has revealed that DDIT4 expression was much higher in nasopharyngeal carcinoma (NPC) and HNSCC tissues than in adjacent tissues 38,39 . Zhao et al found that DDIT4 overexpression promotes the proliferation, migration, invasion and inhibits the apoptosis of NPC cells by partially activating the mTOR signaling pathway 39 .…”

Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma

“…Moreover, in HNSCC, transcriptomic signatures provide promising results with a potential therapeutic impact [ 46 ]. Here, we describe the RNA-seq results from three different HNSCC cell lines, according to their location (laryngeal, pharyngeal and metastatic pharyngeal cells).…”

Homeobox‐D 1 and FTO form a transcriptional–epigenetic feedback loop to promote head and neck cancer proliferation

“…Head and neck squamous cell carcinoma (HNSC) is a common malignant solid tumor that lacks effective treatment options, especially targeted therapies (Mody et al, 2021; Noronha et al, 2022). Although cumulative studies have revealed that human papillomavirus (HPV) infection, mammalian target of rapamycin signaling dysregulation, epidermal growth factor receptor amplification, and TP53 mutation are risk factors for HNSC and participate in tumor development, clinical trials based on these pan‐cancer oncogenic factors have not been very satisfactory (Nathan et al, 2022; Rodriguez et al, 2022; Schinke et al, 2022). Developing efficient therapeutic strategies for HNSC patients based on the concept of precision medicine remains a great challenge (Gu et al, 2022).…”