Prognosis Of Head And Neck Squamous Cell Carcinoma Research Articles

A pyroptosis-related lncRNA risk model for the prediction of prognosis and immunotherapy response in head and neck squamous cell carcinoma

BackgroundRecent research has highlighted pyroptosis as a key factor in cancer progression. This study aims to explore the association between pyroptosis-related signatures and overall survival (OS) in head and neck squamous cell carcinoma (HNSC) and develop a pyroptosis-related long non-coding RNA (lncRNA) risk model to predict prognosis and response to immunotherapy in HNSC.MethodsWe extracted expression data for 18 pyroptosis-related genes and identified lncRNA probes specific to HNSC by using datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Consensus clustering was performed to categorize HNSC patients into distinct subtypes. A six-lncRNA risk score model was constructed through univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. We evaluated the predictive ability of the lncRNA model for patients’ survival and immunotherapy response. Gene expression was evaluated using immunohistochemistry (IHC) and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR).ResultsOur analysis revealed two distinct pyroptosis-related subtypes in HNSC patients, Cluster A and Cluster B. Notably, patients in Cluster B exhibited significantly poorer overall survival compared to those in Cluster A. Through differential expression analysis, we identified six lncRNAs (AC002331.1, CTA-384D8.35, RP11-291B21.2, AC006262.5, RP1-27K12.2, and RP11-54H7.4) that were differentially expressed between these clusters. A 6-lncRNA risk score model was developed, which successfully stratified patients into high- and low-risk groups with distinct overall survival outcomes. Validation using RT-qPCR confirmed the differential expression of these six lncRNAs in HNSC tumor tissues compared to adjacent normal tissues, we found that the expression of CTA-384D8.35 was significantly increased in the tumor group (t=-6.203, P<0.001). Furthermore, the 6-lncRNA risk score model demonstrated a significant association with patient response to immunotherapy, with the low-risk group exhibiting a higher objective response rate to immune checkpoint blockade (ICB) therapy and longer survival compared to the high-risk group.ConclusionOur study underscores the role of pyroptosis signatures in HNSC prognosis and identifies two distinct pyroptosis subtypes with differing survival outcomes. The six-lncRNA risk score model offers a valuable tool for predicting patient prognosis and potential benefits from ICB therapy. These findings highlight the importance of pyroptosis and associated lncRNAs in the tumor microenvironment, paving the way for novel targeted therapies in HNSC.

Unveiling Biomarkers in Head and Neck Squamous Cell Carcinoma through Bioinformatics: The Role of SPP1 and KRT78

Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer, ranking sixth in global cancer incidence. Identifying molecular drivers of tumorigenesis and metastasis is essential for early detection and treatment. This study analyzed gene expression profiles from three datasets (GSE6791, GSE29330, and GSE58911) to identify differentially expressed genes (DEGs) in HNSCC. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to functionally annotate these DEGs. A protein–protein interaction (PPI) network was constructed for selecting hub genes using the STRING database. Finally, hub gene and protein expression levels were evaluated in patients with HNSCC, along with their association with overall survival. Our analysis identified twenty-eight co-DEGs comprising eight up-regulated and twenty down-regulated genes, primarily involved in extracellular matrix (ECM) organization, proteolysis, ECM disassembly, and keratinization processes. Furthermore, the PPI network revealed eight hub genes based on their high degree of connectivity. Notably, SPP1 demonstrated up-regulation, while KRT78 was down-regulated in HNSCC. Remarkably, the expression levels of these hub genes correlated with tumor grade, clinical cancer stage, and poor prognosis in HNSCC. Our findings hold significant clinical potential for early diagnosis and the development of novel therapeutic targets for patients with HNSCC.

Identification and validation of M2 macrophage-related gene signature as a novel prognostic model for head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous tumor. Commonly used tumor staging don’t sufficiently and accurately assess the prognosis of HNSCC patients, resulting in a lack of guidance for clinical treatment decisions. M2 macrophage infiltration has been shown to be strongly associated with the tumor prognosis. In this study, we used the Cancer Genome Atlas (TCGA) data to screen for genes co-expressed with M2 macrophages in HNSCC. We used univariate Cox regression to screen out the genes associated with HNSCC prognosis, and constructed a HNSCC prognosis model by Lasso regression analysis. The results confirmed that the model had good predictive value and accuracy for the prognosis of HNSCC patients by survival analysis, ROC curve and nomogram. We divided the HNSCC samples into high-risk and low-risk groups according to the risk score, and the results showed that patients in the high-risk group were more prone to genetic mutations and had a higher tumor mutational burden. In addition, there were significant differences between risk groups in terms of immune cell infiltration and drug sensitivity. The HNSCC prognostic model established in this study may provide guidance for clinical therapeutic decision-making and provide a theoretical foundation for the development of new immunotherapy methods.

The prognostic value of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma: A systematic review and meta-analysis

Head and neck squamous cell carcinoma (HNSCC) is experiencing a rising incidence and mortality worldwide, emphasizing the need for reliable prognostic markers. Tumor-infiltrating lymphocytes (TILs) have emerged as a promising biomarker for predicting HNSCC prognosis, yet no systematic reviews have exclusively focused on hematoxylin and eosin (H&E)–stained formalin-fixed paraffin-embedded (FFPE) samples, which are routinely used in clinical practice. This systematic review and meta-analysis followed the PRISMA guidelines to examine the prognostic value of TILs in HNSCC using H&E-stained FFPE samples. Data were pooled from 43 studies, including 26 studies in a meta-analysis, analyzing 5037 HNSCC samples. We found that a high TIL count associated with a significantly improved overall survival (OS) (HR 0.47, 95 % CI 0.41–0.55, p < 0.0001), disease-free survival (DFS) (HR 0.55, 95 % CI 0.41–0.55, p < 0.0001), and disease-specific survival (DSS) (HR 0.58, 95 % CI 0.46–0.73, p < 0.0001). The heterogeneity was moderate for the pooled analysis (OS: I² = 40 %; DFS: I² = 39 %; DSS: I² = 51 %), but low for the subgroup analysis based on tumor site in oral, oropharyngeal, laryngeal, and nasopharyngeal cancer (OS and DFS: I² = 0–14 %). This review is the first to systematically evaluate TILs in HNSCC using H&E-stained samples, confirming their prognostic value. A high TIL count is associated with improved survival outcomes, suggesting their potential as prognostic biomarkers in clinical settings.

Development and Validation of a Cholesterol-related Gene Signature for Prognostic Assessment in Head and Neck Squamous Cell Carcinoma.

This study seeks to develop a prognostic risk signature for head and neck squamous cell carcinoma (HNSCC) based on cholesterol-related genes (CholRG), aiming to enhance prognostic accuracy in clinical practice. HNSCC poses significant challenges due to its aggressive behavior and limited response to standard treatments, resulting in elevated morbidity and mortality rates.In order to improve prognostic prediction in HNSCC, our study is inspired by the realization that cholesterol metabolism plays a critical role in accelerating the progression of cancer. To this end, we are developing a unique risk signature using CholRG. The aim of this study was to create a CholRG-based risk signature to predict HNSCC prognosis, aiding in clinical decision-making accurately. The TCGA HNSCC dataset, along with GSE41613 and GSE65858, was obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. A CholRG-based risk signature was then developed and validated across various independent HNSCC cohorts. Moreover, a nomogram model incorporating CholRG-based risk signature was established. Additionally, functional enrichment analysis was conducted, and the immune landscapes of the high- and low-risk groups were compared. Finally, in vitro experiments were performed using lipid-based transfection to deliver siRNAs targeting ACAT1 to SCC1 and SCC23 cell lines, further examining the effects of ACAT1 knockdown on these cells. Utilizing RNA-seq, microarray, and clinical data from public databases, we constructed and validated a CholRG-based risk signature that includes key genes such as ACAT1, CYP19A1, CYP27A1, FAXDC2, INSIG2, PRKAA2, and SEC14L2, which can effectively predict the clinical outcome of HNSCC. Additionally, our findings were reinforced by a nomogram model that integrates the risk score with clinical variables for more clinically practical prognostic assessment. In addition, patients at high risk show hypoxia and increased oncogenic pathways such as mTORC1 signaling, as well as a suppressed immune microenvironment marked by a reduction in the infiltration of important immune cells. Notably, in vitro experiments showed that ACAT1 depletion significantly suppressed the proliferation, colony formation, and invasion capabilities of HNSCC cells, confirming ACAT1's role in promoting malignancy. Collectively, our study not only underscores the importance of cholesterol metabolism in HNSCC pathogenesis but also highlights the CholRG-based risk signature as a promising tool for enhancing prognostic accuracy and personalizing therapeutic strategies.

Exploring the Mechanism of Centipeda minima in Treating Nasopharyngeal Carcinoma Based on Network Pharmacology.

Centipeda minima (CM) is a traditional Chinese herbal medicine used for the treatment of sinusitis and rhinitis, and it possesses anti-cancer properties. However, the mechanism of CM in the treatment of nasopharyngeal carcinoma (NPC) remains unclear. This study aimed to explore the mechanism of CM in the treatment of NPC using a network pharmacology approach. The active components and targets of CM and NPC were screened using TCMSP, SwissTarget, and GeneCards database. The association between CM components and NPC targets or pathways was analyzed using String, Cytoscape 3.9.1, David 6.7, and AutoDock Vina. The Sangerbox platform was used to conduct differential expression and Kaplan-Meier survival analysis of core genes. We identified 17 active compounds of CM and 146 corresponding targeted proteins in NPC. These targets may modulate pathways in cancer, PI3K-Akt, apoptosis, prolactin, relaxin, and TNF signaling. The top 5 core genes of the PPI network were found to be AKT1, STAT3, CASP3, EGFR, and SRC, which may be the main targets of CM in treating NPC. Molecular docking confirmed the binding energies of quercetin with CASP3, 8-Hydroxy-9,10-diisobutyryloxythymol with AKT1, and plenolin with AKT1, which were particularly low, suggesting robust and stable interactions. The expression levels of AKT1, CASP3, EGFR, SRC, MMP9, CCND1, and PTGS2 were significantly higher in head and neck squamous cell carcinoma (HNSC) samples compared to normal samples. In addition, the hub genes could predict the prognosis of HNSC as the Kaplan-Meier survival curve showed that patients with lower expressions of AKT1, STAT3, CASP3, EGFR, MMP9, ESR1, PTGS2, and PPARG had better overall survival. By conducting a network pharmacology approach, we revealed the main ingredients, key targets, and regulatory pathways of Centipeda minima in the treatment of NPC.

The m6A and immune regulatory gene signature predicts the prognosis and correlates with immune infiltration of head and neck squamous cell carcinoma

Recent investigations have underscored the epigenetic modulation of the immune response; however, the interplay between RNA N6-methyladenosine (m6A) modification and immunomodulation in head and neck squamous cell carcinoma (HNSC) remains relatively unexplored. To bridge this knowledge gap, we undertook an extensive examination of the potential contributions of m6A modification and immunomodulation in HNSC. We amalgamated and deduplicated 27 m6A -related genes (m6AGs) and 1342 immune regulation-related genes (IMRGs), resulting in a comprehensive dataset encompassing 1358 genes. This dataset was scrutinized for m6A modification and immunomodulatory patterns within HNSC specimens. Employing Cox regression analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) technique, we developed a prognostic risk model for m6A regulator-mediated methylation modification and immunomodulation-related differentially expressed genes (m6A&IMRDEGs). Our differential expression analysis delineated 29 m6A&IMRDEGs, and Weighted Gene Co-expression Network Analysis (WGCNA) elucidated two module genes (IL11 and MMP13) subjected to correlation analysis. The prognostic prediction models revealed that the clinical predictive efficacy peaked for 1-year forecasts, followed sequentially by 3-year and 5-year predictions. The risk scores derived from the model adeptly categorized HNSC patients into high- and low-risk cohorts, with the high-risk group exhibiting a more unfavorable prognosis. Protein-Protein Interaction (PPI) analysis identified 7 hub genes implicated in m6A and immune regulation, namely BPIFB1, BPIFB2, GP2, MUC5B, MUC7, PIP, and SCGB3A1. Furthermore, we noted marked disparities in the expression profiles of 18 immune cell types between the high- and low-risk groups. Our results substantiate that the clustering subpopulations and risk models associated with m6A and immune regulatory genes portend a poor prognosis in HNSC. The risk score emerges as a potent prognostic biomarker and predictive metric for HNSC patients. A thorough assessment of m6A and immune regulatory genes in HNSC will augment our comprehension of the tumor immune microenvironment and facilitate the advancement of HNSC therapeutics.

Integrative analysis of FADS3 as a marker for prognosis and immunity in head and neck squamous cell carcinoma

BackgroundLong-chain polyunsaturated fatty acid formation requires fatty acid desaturase (FADS), which is strongly linked to cancer progression. Nevertheless, it's unclear how FADS3 functions in head and neck squamous cell carcinoma (HNSCC). MethodsHNSCC cases were retrieved from TCGA and GEO databases, and FADS members with transcriptionally differential expression were identified. Clinical survival, tumor microenvironment (TME), and potential pathogenic mechanism in HNSCC were also investigated. These results were validated using tissue staining, flow cytometry and functional studies in HNSCC cell lines. ResultsWhen comparing HNSCC to normal epithelial tissues, FADS3 expression was much higher in the former. FADS3 upregulation was correlated with poor clinical outcomes. FADS3 was an independent prognostic factor for poor overall survival in HNSCC patients. KEGG, GO, and GSEA revealed that FADS3 expression correlated with several immune-related pathways and the epithelial-mesenchymal transition (EMT). Knocking down FADS3 restrained HNSCC cell proliferation, migration, invasion, and EMT. Single-cell dataset analysis showed an association between FADS3 and TME features. Further investigation revealed that FADS3high tumor was accompanied with less CD8+ T cells in situ tissue and peripheral blood. FADS3 was positively correlated with immune-related molecules and could predict the adverse efficacy of immunotherapy. Finally, we constructed a CYTOR/hsa-let-7c-5p axis regulating FADS3 expression in HNSCC progression. ConclusionsFADS3 may represent a target for treatment in HNSCC, which is linked to prognosis, EMT, immune infiltration, and ceRNA regulatory network of HNSCC.

Unravelling the Complexity of HNSCC Using Single-Cell Transcriptomics.

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and the most common form of head and neck cancer, posing significant challenges for disease management. The objective of this review is to assess the utility of single-cell RNA sequencing (scRNAseq) in addressing these challenges by enabling a detailed characterization of the tumor microenvironment (TME) at the cellular level. This review compiles and analyzes current strategies that utilize scRNAseq and other single-cell technologies in HNSCC research. For HNSCC etiology, scRNAseq allows for the construction of cellular atlases, characterization of different cell types, and investigation of genes and processes involved in cancer initiation, development, and progression within the TME. In terms of HNSCC diagnosis and prognosis, the resolution offered by scRNAseq enables the identification of cell type-specific signatures, enhancing prognostic models and disease stratifiers for patient outcome assessments. Regarding HNSCC treatment, scRNAseq provides insights into cellular responses to various treatments, including radiotherapy, chemotherapy, and immunotherapy, contributing to a better understanding of treatment efficacy and patient outcomes. This review highlights the contributions of scRNAseq to HNSCC research, addressing its cellular and biological complexity, and emphasizes its potential for advancing research and clinical practice in other cancer types.

Potential Prognostic Role of Protein Kinase D Isoforms in Head and Neck Cancers.

Head and neck squamous cell carcinomas (HNSCC) are among the most common malignancies in men worldwide. Nevertheless, their clinical management is hampered by the limited availability of reliable predictive and prognostic biomarkers. Protein kinase D (PKD) isoforms contribute to major cellular processes. However, their potential role in HNSCC has not been studied systematically, which is the focus of this study. A total of 63 therapy-naive patients with squamous cell carcinoma were consecutively enrolled. Tissue microarray duplicate cores from each case were tested in situ for PKD1, PKD2, and PKD3 expression using immunohistochemistry, and the results were correlated with clinicopathological parameters. We found a high frequency of PKD1/PKD2 positive cases in oropharyngeal and PKD2 positive cases in laryngeal localizations. Only high PKD2 levels were statistically linked to elevated tumor grades, more advanced TNM (3-4) tumor stages, and p16INK4a expression, while elevated PKD3 levels were associated with favorable disease-specific survival. Both PKD2 and PKD3 have been proposed to promote tumor cell proliferation, migration/invasion, and angiogenesis. However, the role of PKD3 was elusive in some cancers. Our findings suggest that testing for PKD isotypes with immunohistochemistry may support the diagnostic estimation of tumor progression and prognosis in HNSCC with a potential therapeutic relevance.

The Role of Single Nucleotide Polymorphisms in MicroRNA Genes in Head and Neck Squamous Cell Carcinomas: Susceptibility and Prognosis.

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers worldwide. The identification of molecular alterations adding to the individual risk of HNSCC development and progression is one of the most important challenges in studies on cancer genetics. MicroRNAs (miRNAs), which belong to the group of important post-transcriptional regulators of human gene expression, seem to be valuable options for consideration as key modifiers of individual cancer risk, and therefore may be helpful in predicting inter-individual differences in cancer risk, response to treatment and prognosis. There have not been many studies focused on the relationship between miRNA variants and HNSCC published in PubMed within the last 15 years. We found and analyzed 30 reviews, meta-analyses and research papers and revealed 14 SNPs which have been reported as significant in the context of HNSCC susceptibility and/or prognosis. These 14 SNPs were located in 13 separate miRNAs. Among them, four were the most frequently studied (miRNA-146, -196, -149 and -499) and have been shown to have the greatest impact on the course of HNSCC. However, the presented results have been conflicting. It must be concluded that, despite the years of studies, there are no conclusive reports demonstrating a significant role of SNPs in miRNAs in the context of the susceptibility to HNSCC or its prognosis.

Enhanced computed tomography radiomics predicts solute carrier family 7, member 11 in head and neck squamous cell carcinoma.

Traditional prognostic indicators for head and neck squamous cell carcinoma (HNSCC), such as clinicopathological features, human papillomavirus status, and imaging examinations, often lack precision in guiding medical therapy. Therefore, discovering novel tumor biomarkers that can accurately assess prognosis and aid in personalized medical treatment for HNSCC is critical. Solute carrier family 7, member 11 (SLC7A11), is implicated in ferroptosis, and various malignant tumor therapies regulate its expression. However, the mechanisms regulating SLC7A11 expression, the transporter activity, and its specific role in controlling ferroptosis in cancer cells remain unknown. Thus, in this study, we aimed to develop an improved computed tomography (CT) radiomics model that could predict SLC7A11 expression in patients with HNSCC. We used patient genomic data and corresponding augmented CT images for prognostic analysis and building models. Further, we investigated the potential molecular mechanisms underlying SLC7A11 expression in the immune microenvironment. Our radiomics model successfully predicted SLC7A11 mRNA expression in HNSCC tissues and elucidated its association with relevant genes and prognostic outcomes. SLC7A11 expression level was high within tumor tissues and was connected to the infiltration of eosinophil, CD8+ T-cell, and macrophages, which was associated with poor overall survival. Our models demonstrated robust predictive power. The distribution of radiomics scores (RAD scores) within the training and validation sets was markedly different between the high- and low-expression groups of SLC7A11. SLC7A11 is likely an important factor in the prognosis of HNSCC. SLC7A11 expression can be predicted effectively and reliably by radiomics models based on enhanced CT.

Development of Chromatin Regulator-related Molecular Subtypes and a Signature to Predict Prognosis and Immunotherapeutic Response in Head and Neck Squamous Cell Carcinoma.

Chromatin regulators (CRs) serve as indispensable factors in tumor biological processes by influencing tumorigenesis and the immune microenvironment and have been identified in head and neck squamous cell carcinoma (HNSCC). Hence, CR-related genes (CRRGs) are considered potential biomarkers for predicting prognosis and immune infiltration in HNSCC. In this study, we established a novel signature for predicting the prognosis and immunotherapeutic response of HSNCC. A total of 870 CRRGs were obtained according to previous studies. Subsequently, patients in the TCGA-HNSC cohort were divided into different clusters based on the expression of prognostic CRRGs. Kaplan‒Meier (K‒M) survival analysis was conducted to compare the prognosis in clusters, and the CIBERSORT and ssGSEA methods assessed the immune infiltration status. In addition, the differences in immunotherapeutic responses were determined based on the TICA database. Furthermore, the differentially expressed CRRGs between clusters were identified, and the predictive signature was established according to the results of univariate Cox, least absolute shrinkage and selection operator regression analysis, and multivariate Cox. The predictive effects of the risk model were evaluated according to the area under the receiver operating characteristic (ROC) curve (AUC) in both the training and external test cohorts. A nomogram was established, and survival comparisons, functional enrichment analyses, and immune infiltration status and clinical treatment assessments were performed. In addition, the hub gene network and related analysis were conducted with the Cytohubba application. Based on the expression of prognostic CRRGs, patients were divided into two clusters, in which Cluster 1 exhibited a better prognosis, more enriched immune infiltration, and a better immunotherapeutic response but exhibited chemotherapy sensitivity. The AUC values of the 1-, 3- and 5- year ROC curves for the risk model were 0.673, 0.732, and 0.692, respectively, as well as 0.645, 0.608, and 0.623 for the test set. In addition, patients in the low-risk group exhibited more immune cell enrichment and immune function activation, as well as a better immunotherapy response. The hub gene network indicated ACTN2 as the core gene differentially expressed between the two risk groups. We identified molecular subtypes and established a novel predictive signature based on CRRGs. This effective CRRS system can possibly provide a novel research direction for exploring the correlation between CRs and HNSCC and requires further experimental validation.

Deciphering COPS5 influence on immune infiltration and prognosis in head and neck squamous cell carcinoma

Head and Neck Squamous Cell Carcinoma (HNSCC) is a widespread malignancy originating from the mucous epithelium of the oral cavity, pharynx, and larynx. Despite advances in diagnostic and therapeutic modalities, the prognosis of HNSCC remains challenging. This study investigates the intricate relationship among COPS5, immune infiltration patterns, and prognostic implications in HNSCC. Through comprehensive analyses of 519 HNSCC cases from TCGA and single-cell data from the GEO database, we utilize the CIBERSORT algorithm to discern immune cell dynamics influenced by COPS5 expression. Notably, Treg cells emerge as a central point in the interplay between COPS5 and immune modulation. Further analyses, encompassing differential gene expression, immune-related gene set enrichment, and protein-protein interaction networks, elucidate the molecular landscape associated with COPS5 in HNSCC. A prognostic risk model, incorporating CD27, TNFRSF4, FADD, and PSMD14, is formulated and validated across diverse datasets. The model demonstrates robust predictive power, underscoring its potential as a valuable prognostic tool. These genes, essential for immune regulation and cell cycle control, provide insights into the intricate mechanisms influencing HNSCC progression. In conclusion, this study not only reveals the impact of COPS5 on immune dynamics in HNSCC but also introduces a concise and effective prognostic model.

Prognostic and chemotherapeutic implications of a novel four-gene pyroptosis model in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers. Chemotherapy remains one dominant therapeutic strategy, while a substantial proportion of patients may develop chemotherapeutic resistance; therefore, it is particularly significant to identify the patients who could achieve maximum benefits from chemotherapy. Presently, four pyroptosis genes are reported to correlate with the chemotherapeutic response or prognosis of HNSCC, while no study has assessed the combinatorial predicting efficacy of these four genes. Hence, this study aims to evaluate the predictive value of a multi-gene pyroptosis model regarding the prognosis and chemotherapeutic responsiveness in HNSCC. By utilizing RNA-sequencing data from The Cancer Genome Atlas database and the Gene Expression Omnibus database, the pyroptosis-related gene score (PRGscore) was computed for each HNSCC sample by performing a Gene Set Variation Analysis (GSVA) based on four genes (Caspase-1, Caspase-3, Gasdermin D, Gasdermin E). The prognostic significance of the PRGscore was assessed through Cox regression and Kaplan-Meier survival analyses. Additionally, chemotherapy sensitivity stratified by high and low PRGscore was examined to determine the potential association between pyroptosis activity and chemosensitivity. Furthermore, chemotherapy sensitivity assays were conducted in HNSCC cell lines in vitro. As a result, our study successfully formulated a PRGscore reflective of pyroptotic activity in HNSCC. Higher PRGscore correlates with worse prognosis. However, patients with higher PRGscore were remarkably more responsive to chemotherapy. In agreement, chemotherapy sensitivity tests on HNSCC cell lines indicated a positive association between overall pyroptosis levels and chemosensitivity to cisplatin and 5-fluorouracil; in addition, patients with higher PRGscore may benefit from the immunotherapy. Overall, our study suggests that HNSCC patients with higher PRGscore, though may have a less favorable prognosis, chemotherapy and immunotherapy may exhibit better benefits in this population.

Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma

Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 level negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.

Insights into metastatic roadmap of head and neck cancer squamous cell carcinoma based on clinical, histopathological and molecular profiles.

The incidence of head and neck cancer (HNC), constituting approximately one in ten cancer cases worldwide, affects approximately 644,000 individuals annually. Managing this complex disease involves various treatment modalities such as systemic therapy, radiation, and surgery, particularly for patients with locally advanced disease. HNC treatment necessitates a multidisciplinary approach due to alterations in patients' genomes affecting their functionality. Predominantly, squamous cell carcinomas (SCCs), the majority of HNCs, arise from the upper aerodigestive tract epithelium. The epidemiology, staging, diagnosis, and management techniques of head and neck squamous cell carcinoma (HNSCC), encompassing clinical, image-based, histopathological and molecular profiling, have been extensively reviewed. Lymph node metastasis (LNM) is a well-known predictive factor for HNSCC that initiates metastasis and significantly impacts HNSCC prognosis. Distant metastasis (DM) in HNSCC has been correlated to aberrant expression of cancer cell-derived cytokines and growth factors triggering abnormal activation of several signaling pathways that boost cancer cell aggressiveness. Recent advances in genetic profiling, understanding tumor microenvironment, oligometastatic disease, and immunotherapy have revolutionized treatment strategies and disease control. Future research may leverage genomics and proteomics to identify biomarkers aiding individualized HNSCC treatment. Understanding the molecular basis, genetic landscape, atypical signaling pathways, and tumor microenvironment have enhanced the comprehension of HNSCC molecular etiology. This critical review sheds light on regional and distant metastases in HNSCC, presenting major clinical and laboratory features, predictive biomarkers, and available therapeutic approaches.

Effect of cancer‐associated fibroblasts on prognosis and immune infiltration in head and neck squamous cell carcinoma

AbstractCancer‐associated fibroblasts (CAFs) are the center of cross‐communication between various cells in the tumor stroma. However, how CAFs‐associated genes play an important role in Head and neck squamous cell carcinoma (HNSCC) prognosis has not been reported. Transcriptome data were downloaded from TCGA and GEO databases. Devtools, DPIC, xCell, MCPcounter, and Estimate packages were used to calculate CAFs scores and immune infiltration. Prognosis and weighted gene coexpression network analysis (WGCNA) analysis were performed between high or low risk populations based on CAF scores. Hub genes were identified, intersected, and enriched between TCGA and GEO databases. CAFs related genes were used to construct a prognostic model and the tumor immune dysfunction and exclusion database was used to evaluate the immune infiltration. Drug sensitivity, difference analysis and the HPA database were used to identify sensitive drugs and verify their expression. TCGA and GEO data suggested that CAFs scores had a role in HNSCC prognosis prediction. Based on CAFs scores, WGCNA and core gene enrichment analysis were performed to construct a CAFs‐related prognostic model. The prognostic model composed of a total of 12 CAFs genes could predict the prognosis well and was validated in the validation dataset, demonstrating its applicability to external data. According to the model, although there was no statistical difference in immune escape between the high and low risk groups, the proportion of patients who responded to immunotherapy was different. Drug sensitivity also differed between the two groups. This study suggests that CAFs associated genetic signatures may help to optimize risk stratification and provide new insights into individualized cancer treatment.

Identification of two distinct head and neck squamous cell carcinoma subtypes based on fatty acid metabolism-related signatures: Implications for immunotherapy and chemotherapy.

The dysregulation of lipid metabolism is a critical factor in the initiation and progression of tumors. In this investigation, we aim to characterize the molecular subtypes of head and neck squamous cell carcinoma (HNSCC) based on their association with fatty acid metabolism and develop a prognostic risk model. The transcriptomic and clinical data about HNSCC were obtained from public databases. Clustering analysis was conducted on fatty acid metabolism genes (FAMG) associated with prognosis, utilizing the non-negative matrix factorization algorithm. The immune infiltration, response to immune therapy, and drug sensitivity between molecular subtypes were evaluated. Differential expression genes were identified between subtypes, and a prognostic model was constructed using Cox regression analyses. A nomogram for HNSCC was constructed and evaluated. Thirty FAMGs have been found to exhibit differential expression in HNSCC, out of which three are associated with HNSCC prognosis. By performing clustering analysis on these 3 genes, 2 distinct molecular subtypes of HNSCC were identified that exhibit significant heterogeneity in prognosis, immune landscape, and treatment response. Using a set of 7778 genes that displayed differential expression between the 2 molecular subtypes, a prognostic risk model for HNSCC was constructed comprising 11 genes. This model has the ability to stratify HNSCC patients into high-risk and low-risk groups, which exhibit significant differences in prognosis, immune infiltration, and immune therapy response. Moreover, our data suggest that this risk model is negatively correlated with B cells and most T cells, but positively correlated with macrophages, mast cells, and dendritic cells. Ultimately, we constructed a nomogram incorporating both the risk signature and radiotherapy, which has demonstrated exceptional performance in predicting prognosis for HNSCC patients. A molecular classification system and prognostic risk models were developed for HNSCC based on FAMGs. This study revealed the potential involvement of FAMGs in modulating tumor immune microenvironment and response to treatment.

Combined spatial Keratin expression profiles at the invasive front represent a prognostic classifier for head and neck cancer

Keratin proteins are intermediate filaments that provide mechanical support and guide a plethora of important functions in epithelial cells. Although Keratins can be effectively used to characterize and differentiate cell lineages in many epithelia, it is still unclear if combinations of Keratin types and their spatial expression patterns can aid prognostication of head and neck squamous cell carcinoma (HNSCC). Here, we have assessed a panel of Keratin markers in four HPV negative HNSCC patient-derived organoid (PDO) models and their corresponding primary patient tissue to define spatial expression profiles of basal and supra-basal Keratins during invasion in Collagen-I matrices. Based on these profiles we have devised a scoring classification consisting of the following profiles: (i) no expression (Negative), (ii) uniform expression (Homogenous), (iii) heterogeneous expression (Mosaic), (iv) expression in the tumor core (Core), and (v) expression at the invasive front (Edge). Subsequently, this 5-tier system was validated in a well-documented tissue cohort of 157 HNSCC patients. We observe that patients with a Keratin 13 (K13) Edge profile have a significantly better prognosis than patients with K13 Core expression or K13 Negative tumors. Interestingly, we also find that K14 mosaicism strongly correlates with a favorable prognosis. We show that the absence of K13 from the tumor edge, in combination with K14 homogenous expression is a strong biomarker for poor prognosis in HNSCC. In short, our work indicates that defining the spatial expression patterns of basal and supra-basal markers in invasive HNSCC can benefit patient prognostication.