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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.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with high mortality. The main reasons for treatment failure are a low rate of early diagnosis, high relapse rates, and distant metastasis with poor outcomes. These are largely due to a lack of diagnostic, prognostic, and predictive biomarkers in HNSCC. DNA methylation has been demonstrated to play an important role in the pathogenesis of HNSCC, and recent studies have also valued DNA methylation as a potential biomarker in HNSCC. This review summarizes the current knowledge on DNA methylation profiles in HPV-positive and HPV-negative HNSCC and how these may contribute to the pathogenesis of HNSCC. It also summarizes the potential value of DNA methylation as a biomarker in the diagnosis, prognosis, and prediction of the response to therapy. With the recent immunotherapy era in head and neck treatment, new strategies to improve immune responses by modulating TIMEs have been intensely investigated in early-phase trials. Therefore, this study additionally summarizes the role of DNA methylation in the regulation of TIMEs and potential predictive immunotherapy response biomarkers. Finally, this study reviews ongoing clinical trials using DNA methylation inhibitors in HNSCC.

Yippee‐like 3 (YPEL3) has been implicated in the regulation of apoptosis, proliferation, and invasion in various cancers, but its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we integrated pan‐cancer data, TCGA/GEO transcriptomes, DNA methylation profiles, and single‐cell RNA sequencing to explore YPEL3's expression, prognosis, and immune relevance in HNSCC. YPEL3 was downregulated in tumor tissues and correlated with better overall survival, particularly in advanced‐stage patients. Functional assays confirmed that YPEL3 suppressed proliferation, migration, and invasion while promoting apoptosis in vitro; its knockdown accelerated tumor growth in vivo. Bulk transcriptomics and TIMER analysis revealed that high YPEL3 expression was associated with increased stromal and immune infiltration, including CD8 + T cells. Single‐cell analysis identified an epithelial subcluster (Epi.C3) enriched for YPEL3, expanded in tumors, and linked to poor prognosis. Mechanistically, YPEL3‐high epithelial cells secreted CXCL16, interacting with CXCR6 on CD8 + T cells to promote immune engagement. YPEL3 regulated CXCL16 via CREB1 but not TFAP2C. Co‐culture assays showed that epithelial YPEL3 modulated the CXCL16–CXCR6 axis in T cells. In vivo, YPEL3 loss was associated with reduced CD8 + T‐cell infiltration and impaired CD8 + T‐cell effector function, as indicated by decreased Granzyme B, Perforin, IFN‐γ, and TNF‐α. Together, these findings identify YPEL3 as a tumor suppressor and an important mediator of epithelial–immune crosstalk in HNSCC, linking epithelial differentiation‐associated states to antitumor immunity through the CREB1/CXCL16/CXCR6 axis.

Human papillomavirus HPV-positive head and neck squamous cell carcinoma (HPV+ HNSCC) exhibits distinct tumor biology and immune microenvironment characteristics. Understanding cellular heterogeneity and identifying immune-associated biomarkers are crucial for elucidating the pathogenesis of HPV+ HNSCC and discovering novel therapeutic targets. A scRNA-seq dataset (GSE139324) of HPV+ HNSCC tumor tissues was analyzed using the Seurat and Harmony packages for data preprocessing, dimensionality reduction, and clustering. Bulk RNA-seq dataset (GSE112026) was used for differential expression and immune infiltration analyses. Functional enrichment analysis and GSEA were performed, followed by drug prediction and molecular docking validation to identify potential biomarkers and therapeutic agents for HPV+ HNSCC. scRNA-seq analysis revealed seven major cell types within the TME. Monocyte subpopulations categorized into three subpopulations: classical, intermediate, and non-classical. Four classical monocyte-specific genes (CYP1B1, THBS1, NEAT1, VCAN) were significantly upregulated in tumor tissues and showed strong positive correlations with immune infiltration metrics. GSEA revealed enrichment of tumor-related pathways (e.g., EMT, hypoxia) in samples with high expression of these genes. Trichostatin A was predicted as a candidate drug, and molecular docking confirmed strong binding affinity between CYP1B1 and THBS1. Our integrative single-cell and bulk transcriptomic analyses revealed distinct monocyte heterogeneity and identified classical monocyte-associated biomarkers potentially involved in the immune regulation and progression of HPV+ HNSCC. Trichostatin A may become a therapeutic agent targeting key monocyte-related genes. [Display omitted]

Head and neck squamous cell carcinoma (HNSCC), which originates in the head or neck tissues, is characterized by high rates of recurrence and metastasis. Inflammation is important in HNSCC prognosis. Inflammatory cells and their secreted factors contribute to the various stages of HNSCC development through multiple mechanisms. In this review, the mechanisms through which inflammatory factors, signaling pathways, and cells contribute to the initiation and progression of HNSCC have been discussed in detail. Furthermore, the diagnostic and therapeutic potential of targeting inflammation in HNSCC has been discussed to gain new insights into improving patient prognosis. Keywords: inflammation, head and neck squamous cell carcinoma, HNSCC, mediators, progression, therapy

BackgroundHead and neck squamous cell carcinoma (HNSCC), the most common head and neck cancer, is highly aggressive and heterogeneous, resulting in variable prognoses and immunotherapeutic outcomes. Natural killer (NK) cells play essential roles in malignancies’ development, diagnosis, and prognosis. The purpose of this study was to establish a reliable signature based on genes related to NK cells (NRGs), thus providing a new perspective for assessing immunotherapy response and prognosis of HNSCC patients.MethodsIn this study, NRGs were used to classify HNSCC from the TCGA-HNSCC and GEO cohorts. The genes were evaluated using univariate cox regression analysis based on the differential analysis of normal and tumor samples in TCGA-HNSCC conducted using the “limma” R package. Thereafter, we built prognostic gene signatures using LASSO-COX analysis. External validation was carried out in the GSE41613 cohort. Immunity analysis based on NRGs was performed via several methods, such as CIBERSORT, and immunotherapy response was evaluated by TIP portal website.ResultsWith the TCGA-HNSCC data, we established a nomogram based on the 17-NRGs signature and a variety of clinicopathological characteristics. The low-risk group exhibited a better effect when it came to immunotherapy.Conclusions17-NRGs signature and nomograms demonstrate excellent predictive performance and offer new perspectives for assessing pre-immune efficacy, which will facilitate future precision immuno-oncology research.

Human papillomavirus (HPV)-related malignancies are responsible for almost all cases of cervical cancer in women, and over 50% of all cases of head and neck carcinoma. Worldwide, HPV-positive malignancies account for 4.5% of the global cancer burden, or over 600,000 cases per year. HPV infection is a pressing public health issue, as more than 80% of all individuals have been exposed to HPV by age 50, representing an important target for vaccine development to reduce the incidence of cancer and the economic cost of HPV-related health issues. The approval of Gardasil[R] as a prophylactic vaccine for high-risk HPV 16 and 18 and low-risk HPV6 and 11 for people aged 11-26 in 2006, and of Cervarix[R] in 2009, revolutionized the field and has since reduced HPV infection in young populations. Unfortunately, prophylactic vaccination does not induce immunity in those with established HPV infections or HPV-induced neoplasms, and there are currently no therapeutic HPV vaccines approved by the US Food and Drug Administration. This comprehensive review will detail the progress made in the development of therapeutic vaccines against high-risk HPV types, and potential combinations with other immunotherapeutic agents for more efficient and rational designs of combination treatments for HPV-associated malignancies. Keywords: human papillomavirus, HPV, therapeutic vaccine, cervical cancer, head and neck squamous cell carcinoma, HNSCC, combination immunotherapy

Head and neck cancer (HNC) cases are increasing globally, with resistance to immunotherapies such as nivolumab posing a significant challenge. This systematic review examines the mechanisms of nivolumab resistance in HNC, with a focus on intrinsic tumor factors, the immunosuppressive tumor microenvironment (TME), and immune checkpoint dysregulation. Intrinsic mechanisms, such as mutations that impair antigen presentation and MYC amplification, reshape the TME to promote immune evasion. The tumor microenvironment, enriched with immunosuppressive cells such as tumor-associated macrophages and myeloid-derived suppressor cells, further compromises nivolumab’s effectiveness. Moreover, cancer cells exploit immune checkpoints, including programmed death-ligand 1 (PD-L1), T-cell immunoglobulin and mucin domain-3, and LAG-3, to evade immune surveillance. Identifying predictive biomarkers, such as MYC amplification and PD-L1 expression, is essential for developing personalized treatments. This review underscores the complex nature of nivolumab resistance and the urgent need for comprehensive therapeutic strategies to improve outcomes in HNC patients.

Background Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined. Methods The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC. Results We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability. Conclusions Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.

Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2 . LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.