RESUMEN

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein­Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5­year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Asunto(s)

Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Microambiente Tumoral , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinogénesis/genética , Pronóstico , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/patología

RESUMEN

Background: Most head and neck squamous cell carcinoma (HNSCC) patients are diagnosed at an advanced local stage. While immunotherapy has improved survival rates, only a minority of patients respond durably to targeted immunotherapies, posing substantial clinical challenges. We investigated the heterogeneity of the tumor microenvironment in HNSCC cohorts before and after immunotherapy by analyzing single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing datasets retrieved from public databases. Methods: We constructed a single-cell transcriptome landscape of HNSCC patients before and after immunotherapy and analyzed the cellular composition, developmental trajectories, gene regulatory networks, and communication patterns of different cell type subpopulations. Additionally, we assessed the expression levels of relevant indicators in HNSCC cells via western blot, ELISA, and fluorescent probe techniques. Results: At the single-cell level, we identified a subpopulation of TP63+ SLC7A5+ HNSCC that exhibited a ferroptosis-resistant phenotype. This subpopulation suppresses ferroptosis in malignant cells through the transcriptional upregulation of SLC7A5 mediated by high TP63 expression, thereby promoting tumor growth and resistance to immunotherapy. The experimental results demonstrated that the overexpression of TP63 upregulated the expression of SLC7A5 and suppressed the concentrations of Fe2+ and ROS in HNSCC cells. By integrating bulk transcriptome data, we developed a clinical scoring model based on TP63 and SLC7A5, which are closely associated with tumor stage, revealing the significant prognostic efficacy of the TP63+ SLC7A5+ HNSCC-mediated ferroptosis mechanism in HNSCC patients. Conclusion: Our research elucidates the TME in HNSCC before and after immunotherapy, revealing a novel mechanism by which TP63+ SLC7A5+ HNSCC inhibits ferroptosis and enhances tumor resistance via TP63-induced SLC7A5 upregulation. These insights lay the foundation for the development of more effective treatments for HNSCC.

Asunto(s)

Ferroptosis , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Ferroptosis/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/inmunología , Línea Celular Tumoral , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transportador de Aminoácidos Neutros Grandes 1/genética , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Microambiente Tumoral/genética , Animales , Ratones , Inmunoterapia/métodos , Análisis de la Célula Individual

RESUMEN

BACKGROUND: HPV status in a subset of HNSCC is linked with distinct treatment outcomes. Present investigation aims to elucidate the distinct clinicopathological features of HPV-positive and HPV-negative HNSCC and investigate their association with the HNSCC patient survival. MATERIALS AND METHODS: The total RNA of exosomes from HPV-positive (93VU147T) and HPV-negative (OCT-1) HNSCC cells was isolated, and the transcripts were estimated using Illumina HiSeq X. The expression of altered transcripts and their clinical relevance were further analyzed using publicly available cancer transcriptome data from The Cancer Genome Atlas (TCGA). RESULTS: Transcriptomic analyses identified 3785 differentially exported transcripts (DETs) in HPV-positive exosomes compared to HPV-negative exosomes. DETs that regulate the protein machinery, cellular redox potential, and various neurological disorder-related pathways were over-represented in HPV-positive exosomes. TCGA database revealed the clinical relevance of altered transcripts. Among commonly exported abundant transcripts, SGK1 and MAD1L1 showed high expression, which has been correlated with poor survival in HNSCC patients. In the top 20 DETs of HPV-negative exosomes, high expression of FADS3, SGK3, and TESK2 correlated with poor survival of the HNSCC patients in the TCGA database. CONCLUSION: Overall, our study demonstrates that HPV-positive and HPV-negative cells' exosomes carried differential transcripts cargo that may be related to pathways associated with neurological disorders. Additionally, the altered transcripts identified have clinical relevance, correlating with patient survival in HNSCC, thereby highlighting their potential as biomarkers and as therapeutic targets.

Asunto(s)

Exosomas , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Exosomas/metabolismo , Exosomas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Neoplasias de Cabeza y Cuello/metabolismo , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Persona de Mediana Edad , Línea Celular Tumoral , Transcriptoma , Pronóstico , Anciano

RESUMEN

Liquid biopsy profiling is gaining increasing promise towards biomarker-led identification and disease stratification of tumours, particularly for tumours displaying significant intra-tumoural heterogeneity (ITH). For head and neck squamous cell carcinoma (HNSCC), which display high levels of genetic ITH, identification of epigenetic modifications and methylation signatures has shown multiple uses in stratification of HNSCC for prognosis, treatment, and HPV status. In this study, we investigated the potential of liquid biopsy methylomics and genomic copy number to profile HNSCC. We conducted multi-region sampling of tumour core, tumour margin and normal adjacent mucosa, as well as plasma cell-free DNA (cfDNA) across 9 HNSCC patients. Collectively, our work highlights the prevalence of methylomic ITH in HNSCC, and demonstrates the potential of cfDNA methylation as a tool for ITH assessment and serial sampling.

Asunto(s)

Variaciones en el Número de Copia de ADN , Metilación de ADN , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Biopsia Líquida/métodos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética

RESUMEN

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

Asunto(s)

Consumo de Bebidas Alcohólicas , Neoplasias de Cabeza y Cuello , Análisis de la Aleatorización Mendeliana , Infecciones por Papillomavirus , Fumar , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Consumo de Bebidas Alcohólicas/efectos adversos , Neoplasias de Cabeza y Cuello/virología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/epidemiología , Fumar/efectos adversos , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/epidemiología , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/epidemiología , Masculino , Femenino , Factores de Riesgo , Papillomaviridae/genética , Persona de Mediana Edad , Estudios de Casos y Controles , Polimorfismo de Nucleótido Simple

RESUMEN

OBJECTIVES: Alcohol drinking is a major risk factor for head and neck cancer (HNC), and this risk may be modified by alcohol dehydrogenase (ADH) genes. The first systematic review and meta-analysis was designed with more studies and added trial sequential analysis and functional analysis for a better understanding of the role of ADH3 polymorphism in HNC patients. METHODS: A search was performed across several databases, including PubMed/Medline, Web of Science, Scopus, and Cochrane Library, up to May 5, 2024, without any restrictions to find pertinent studies. The RevMan 5.3 software was used to calculate the effect sizes. These were expressed as the odds ratio (OR) with a 95 % confidence interval. RESULTS: Twenty-seven articles were included in the meta-analysis. The frequency of *1/*1, *1/*2, and *2/*2 genotypes in cases with HNC was 47.14 %, 41.06 %, and 11.80 %, respectively, and in controls was 50.56 %, 38.29 %, and 11.15 %, respectively. The pooled OR for the allelic model is 1.11 (p = 0.18), for the homozygous model is 0.95 (p = 0.64), for the heterozygous model is 0.99 (p = 0.90), for the dominant model is 1.11 (p = 0.14), and for the recessive model is 0.98 (p = 0.78). In the Asians, the three models showed an increased significant association. In the cancer subtype subgroup, a protective significant association was found in the pharyngeal cancer subtype. CONCLUSIONS: The current analysis suggests that ADH3 polymorphism may not have a significant impact on the risk of HNC, but the polymorphism had an increased risk in Asians and a protective role in pharyngeal cancers.

Asunto(s)

Alcohol Deshidrogenasa , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello , Humanos , Alcohol Deshidrogenasa/genética , Neoplasias de Cabeza y Cuello/genética , Polimorfismo Genético/genética , Factores de Riesgo , Genotipo , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/efectos adversos

RESUMEN

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), is an increasingly prevalent pathology worldwide, especially in developed countries. For diagnosing HPV in HNSCC, the combination of p16 immunohistochemistry (IHC) and polymerase chain reaction (PCR) offers high sensitivity and specificity, with p16 IHC being a reliable initial screen and PCR confirming HPV presence. Advanced techniques like next-generation sequencing (NGS) and RNA-based assays provide detailed insights but are primarily used in research settings. Regardless of HPV status, standard oncological treatments currently include surgery, radiation, and/or chemotherapy. This conventional approach does not account for the typically better prognosis of HPV-positive HNSCC patients, leading to increased chemo/radiation-induced secondary morbidities and reduced quality of life. Therefore, it is crucial to identify and detect HPV positivity and other molecular characteristics of HNSCC to personalize treatment strategies. This comprehensive review aims to summarize current knowledge on various HPV detection techniques and evaluate their advantages and disadvantages, with a focus on developing methodologies to identify new biomarkers in HPV-positive HNSCC. The review discusses direct and indirect HPV examination in tumor tissue, DNA- and RNA-based detection techniques, protein-based markers, liquid biopsy potentials, immune-related markers, epigenetic markers, novel biomarkers, and emerging technologies, providing an overall insight into the current state of knowledge.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Neoplasias de Cabeza y Cuello/virología , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/genética , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Inmunohistoquímica , ADN Viral/genética , ADN Viral/análisis , Reacción en Cadena de la Polimerasa/métodos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética

RESUMEN

Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.

Asunto(s)

Neoplasias de Cabeza y Cuello , Neovascularización Patológica , Carcinoma de Células Escamosas de Cabeza y Cuello , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Animales , Transducción de Señal/efectos de los fármacos

RESUMEN

Telomeres play a crucial role in maintaining chromosomal integrity and regulating the number of cell divisions and have been associated with cellular aging. Telomere length (TL) has been widely studied in manifold cancer types; however, the results have been inconsistent. This systematic review and meta-analysis aims to analyze the evidence on the association between TL and head and neck cancer (HNC) risk. We comprehensively searched the literature in PubMed, Cochrane Library, and Scopus and identified nine eligible studies, which yielded 11 datasets. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to ascertain the strength of the association. On the basis of the median TL, we defined two groups, short TL and long TL, with the latter being the reference group. Our analysis found a significant relationship between short TL and increased HNC risk (OR 1.38, 95% CI: 1.10-1.73, p = 0.005), while significant heterogeneity among the studies was noted. The subgroup analysis on HNC subtypes revealed a significant association between short TL and oral cancers (OR 2.08, 95% CI: 1.23-3.53, p = 0.007). Additionally, subgroup analysis indicates that adjustments for age, sex, and smoking did not affect the significance of our findings. In conclusion, our meta-analysis found evidence for an association between short TL and HNC risk, which could indicate that TL might act as a potential biomarker for HNC risk, but high-quality prospective studies are imperative to validate our findings.

Asunto(s)

Neoplasias de Cabeza y Cuello , Homeostasis del Telómero , Telómero , Humanos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Telómero/genética , Telómero/metabolismo , Factores de Riesgo , Oportunidad Relativa

RESUMEN

Cuproptosis, a copper-dependent programmed cell death process, holds promise for controlling cell death in tumor cells. Autophagy, a fundamental cellular process, has been linked to various aspects of cancer, such as proliferation, migration, and drug resistance. This research is centered on the investigation of autophagy- and cuproptosis-related long noncoding RNAs (lncRNAs) and the establishment of a prognostic model for head and neck squamous cell carcinoma. RNA sequencing data from head and neck squamous cell carcinoma patients in The Cancer Genome Atlas database identified cuproptosis-related lncRNAs via Pearson analysis. Patients were divided into training and testing sets. A prognostic model developed in the training set using univariate-least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression was tested for accuracy. Kaplan-Meier analysis showed high-risk patients had poorer outcomes. Cox regression confirmed the model's risk score as an independent prognostic indicator, with receiver operating characteristic and decision curve analyses validating its predictive accuracy. Thirteen lncRNAs associated with autophagy and cuproptosis were identified through bioinformatics analysis. Lasso regression narrowed this to 3 significant prognostic lncRNAs. Based on median risk scores, patients were classified into high-risk and low-risk groups. Kaplan-Meier survival curves revealed significant differences between these groups (P < .01). Through a set of bioinformatics analyses, we identified 13 autophagy- and cuproptosis-related lncRNAs. By Lasso regression, 3 prognostic-related lncRNAs were further selected. We also investigated these 3 lncRNAs in relation to clinicopathologic features. The principal component analysis visually showed differences between the high-risk and low-risk groups.

Asunto(s)

Autofagia , Neoplasias de Cabeza y Cuello , ARN Largo no Codificante , Carcinoma de Células Escamosas de Cabeza y Cuello , ARN Largo no Codificante/genética , Humanos , Autofagia/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Pronóstico , Estimación de Kaplan-Meier

RESUMEN

In this study, we explore the possibility of inferring characteristics of the tumor immune microenvironment from the blood. Specifically, we investigate two datasets of patients with head and neck squamous cell carcinoma with matched single-cell RNA sequencing (scRNA-seq) from peripheral blood mononuclear cells (PBMCs) and tumor tissues. Our analysis shows that the immune cell fractions and gene expression profiles of various immune cells within the tumor microenvironment can be inferred from the matched PBMC scRNA-seq data. We find that the established exhausted T-cell signature can be predicted from the blood and serve as a valuable prognostic blood biomarker of immunotherapy response. Additionally, our study reveals that the inferred ratio between tumor memory B- and regulatory T-cell fractions is predictive of immunotherapy response and is superior to the well-established cytolytic and exhausted T-cell signatures. These results highlight the promising potential of PBMC scRNA-seq in cancer immunotherapy and warrant, and will hopefully facilitate, further investigations on a larger scale. The code for predicting tumor immune microenvironment from PBMC scRNA-seq, TIMEP, is provided, offering other researchers the opportunity to investigate its prospective applications in various other indications. SIGNIFICANCE: Our work offers a new and promising paradigm in liquid biopsies to unlock the power of blood single-cell transcriptomics in cancer immunotherapy.

Asunto(s)

Neoplasias de Cabeza y Cuello , Análisis de la Célula Individual , Carcinoma de Células Escamosas de Cabeza y Cuello , Transcriptoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Análisis de la Célula Individual/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/patología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Inmunoterapia/métodos , Pronóstico , Perfilación de la Expresión Génica/métodos , Masculino

RESUMEN

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that often develops unnoticed. Typically, these tumors are identified at advanced stages, resulting in a relatively low chance of successful treatment. Anoikis serves as a natural defense against the spread of tumor cells, meaning circumventing anoikis can effectively inhibit tumor metastasis. Nonetheless, studies focusing on anoikis in the context of HNSCC remain scarce. METHODS: Anoikis-related genes (ARGs) were identified by using the GeneCards and Harmonizome databases. Expression data of these genes and relevant clinical features were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A LASSO regression and a prognostic risk score model were developed to determine their prognostic significance. The analysis included the use of the CIBERSORT algorithm to quantify immune and stromal cell presence. Furthermore, in vitro and in vivo, we confirmed the expression and functional roles of proteins and mRNA of genes independently predictive of prognosis. RESULTS: The study identified eight genes linked to prognosis (ANXA5, BAK1, CDKN2A, PPARG, CCR7, MAPK11, CRYAB, CRYBA1) and developed a prognostic model that effectively forecasts the survival outcomes for patients with HNSCC. A higher survival likelihood is associated with lower risk scores. In addition, a significant relationship was found between immune and risk score, and ANXA5 deletion promoted the killing of HNSCC cells by activated CD8+ T cells. During the screening process, 65 different chemotherapeutic drugs were found to have significant differences in IC50 values when comparing high- and low-risk categories. ANXA5 emerged as a gene with independent prognostic significance, exhibiting notably elevated protein and mRNA levels in HNSCC tissue compared to non-tumorous tissue. The suppression of ANXA5 gene activity resulted in a substantial decrease in both the growth and mobility of HNSCC cells. Animal model experiments demonstrated that inhibiting ANXA5 suppressed HNSCC growth and migration in vivo. CONCLUSION: Through bioinformatics, a prognostic risk model of high precision was developed, offering valuable insights into the survival rates and immune responses in patients with HNSCC. ANXA5 is highlighted as a significant prognostic factor among the identified genes, indicating its promise as a potential therapeutic target for those with HNSCC.

Asunto(s)

Movimiento Celular , Proliferación Celular , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Pronóstico , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Proliferación Celular/genética , Ratones , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Anoicis/genética , Biomarcadores de Tumor/genética , Masculino , Femenino

RESUMEN

BACKGROUND: Radiotherapy (RT) is a crucial treatment for head and neck cancer however, it causes adverse reactions to the normal tissue and organs adjacent to target tumor. The present study was carried out to investigate possible association of single nucleotide polymorphism in DNA repair genes with toxicity effects of radiotherapy on normal tissue. METHODS: Three hundred and fifty head and neck cancer patients receiving radiotherapy treatment were enrolled in this study. The adverse after effects of radiotherapy on the normal tissue in the form of skin reactions were recorded. Single nucleotide polymorphisms of APE1 (rs1130409), hOGG1 (rs1052133) and Rad51 (rs1801320, rs1801321) genes were studied by polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing methods and their association with development of severe radio-toxicity effects was evaluated logistic regression analysis. RESULTS: The 172G/T polymorphism of Rad51 was 2.85 times higher and significantly associated with skin reactions (OR=2.85, 95% CI: 1.50-5.41; p=0.001) and severe oral mucositis (OR=4.96, 95% CI: 2.40-10.25; p<0.0001). These results suggested that the polymorphic nature of Rad51 is responsible for risk of radiotherapy adverse effects in HNC patients. The variant 326Cys and heterozygous 326Ser/Cys genotype of hOGG1 was significantly associated with high tumor grade (OR=3.16 95% CI: 1.66-5.99; p=0.0004, and OR=3.97 95% CI: 2.15-7.34; p=<0.0001 respectively). The homozygous variant 172TT genotype of Rad51 showed positive association with poor response of both tumor and nodes towards radiotherapy treatment (p=0.007 and p=0.022). CONCLUSIONS: Interpretation of our results revealed significant association of rs1801321 SNP of Rad51 with development of adverse toxicity reactions in normal tissue of head and neck cancer patients treated with radiotherapy.

Asunto(s)

ADN Glicosilasas , ADN-(Sitio Apurínico o Apirimidínico) Liasa , Neoplasias de Cabeza y Cuello , Polimorfismo de Nucleótido Simple , Recombinasa Rad51 , Humanos , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Masculino , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Femenino , Recombinasa Rad51/genética , Persona de Mediana Edad , ADN Glicosilasas/genética , Estudios de Seguimiento , Pronóstico , Traumatismos por Radiación/genética , Traumatismos por Radiación/etiología , Anciano , Adulto , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patología , Genotipo , Reparación del ADN/genética , Biomarcadores de Tumor/genética , Radioterapia/efectos adversos

RESUMEN

Targeting wild-type epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) never achieved its purported success in cancers such as head and neck squamous cell carcinoma, which are largely EGFR-dependent. We had previously shown that exceptional responders to TKIs have a genetic aberration that results in overexpression of an EGFR splice variant, isoform D (IsoD). IsoD lacks an integral transmembrane and kinase domain and is secreted in extracellular vesicles (EVs) in TKI-sensitive patient-derived cultures. Remarkably, the exquisite sensitivity to TKIs could be transferred to TKI-resistant tumor cells, and IsoD protein in the EV is necessary and sufficient to transfer the phenotype in vitro and in vivo across multiple models and drugs. This drug response requires an intact endocytic mechanism, binding to full-length EGFR, and signaling through Src-phosphorylation within the endosomal compartment. We propose a therapeutic strategy using EVs containing EGFR IsoD as a co-drug to expand the use of TKI therapy to EGFR-driven cancers.

Asunto(s)

Carcinoma de Células Escamosas , Receptores ErbB , Vesículas Extracelulares , Isoformas de Proteínas , Animales , Humanos , Ratones , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Vesículas Extracelulares/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/genética , Fosforilación/efectos de los fármacos , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , /uso terapéutico

RESUMEN

Macrophages played an important role in the progression and treatment of head and neck squamous cell carcinoma (HNSCC). We employed weighted gene co-expression network analysis (WGCNA) to identify macrophage-related genes (MRGs) and classify patients with HNSCC into two distinct subtypes. A macrophage-related risk signature (MRS) model, comprising nine genes: IGF2BP2, PPP1R14C, SLC7A5, KRT9, RAC2, NTN4, CTLA4, APOC1, and CYP27A1, was formulated by integrating 101 machine learning algorithm combinations. We observed lower overall survival (OS) in the high-risk group and the high-risk group showed elevated expression levels in most of the immune checkpoint and human leukocyte antigen (HLA) genes, suggesting a strong immune evasion capacity. Correspondingly, TIDE score positively correlated with risk score, implying that high-risk tumors may resist immunotherapy more effectively. At the single-cell level, we noted macrophages in the tumor microenvironment (TME) predominantly stalled in the G2/M phase, potentially hindering epithelial-mesenchymal transition and playing a crucial role in the inhibition of tumor progression. Finally, the proliferation and migration abilities of HNSCC cells significantly decreased after the expression of IGF2BP2 and SLC7A5 reduced. It also decreased migration ability of macrophages and facilitated their polarization towards the M1 direction. Our study constructed a novel MRS for HNSCC, which could serve as an indicator for predicting the prognosis, immune infiltration and immunotherapy for HNSCC patients.

Asunto(s)

Neoplasias de Cabeza y Cuello , Inmunoterapia , Aprendizaje Automático , Macrófagos , Carcinoma de Células Escamosas de Cabeza y Cuello , Microambiente Tumoral , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Inmunoterapia/métodos , Pronóstico , Macrófagos/inmunología , Macrófagos/metabolismo , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/patología , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Masculino , Línea Celular Tumoral

RESUMEN

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) typically present with a complex anatomical distribution, often accompanied by insidious symptoms. This combination contributes to its high incidence and poor prognosis. It is now understood that the immune features of cellular components within the tumor ecosystem and their complex interactions are critical factors influencing both tumor progression and the effective immune response. METHODS: We obtained single-cell RNA sequencing data of 26,496 cells from three tumor tissues and five normal tissues and performed subsequent analyses. Immunohistochemical staining on tumor sections was used to validate the presence of malignant cells. Additionally, we included bulk RNA sequencing data from 502 HNSCC patients. Kaplan-Meier analysis and the log-rank test were employed to assess predictors of patient outcomes. RESULTS: We identified three epithelial subclusters exhibiting immune-related features. These subclusters promoted the infiltration of T cells, dendritic cells, and monocytes into the tumor microenvironment. Additionally, cancer-associated fibroblasts displayed tumor-promoting and angiogenesis characteristics, contrasting with the predominant antigen-presenting and inflammatory roles observed in fibroblasts from normal tissues. Furthermore, tumor endothelial subsets exhibited a double-sided effect, promoting tumor progression and enhancing the effectiveness of immune response. Finally, follicular helper T cells and T helper 17 cells were found to be significantly correlated with improved outcomes in HNSCC patients. These CD4+ T cell subpopulations could promote the anti-tumor immune response by recruiting and activating B and T cells. CONCLUSION: Our findings provide deeper insights into the immune features of the tumor ecosystem and reveal the prognostic significance of follicular helper T cells and T helper 17 cells. These findings may pave the way for the development of therapeutic approaches.

Asunto(s)

Neoplasias de Cabeza y Cuello , Linfocitos Infiltrantes de Tumor , Análisis de Expresión Génica de una Sola Célula , Carcinoma de Células Escamosas de Cabeza y Cuello , Células Th17 , Microambiente Tumoral , Femenino , Humanos , Masculino , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Linfocitos Infiltrantes de Tumor/inmunología , Pronóstico , RNA-Seq/métodos , Análisis de Expresión Génica de una Sola Célula/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células T Auxiliares Foliculares/inmunología , Células Th17/inmunología , Microambiente Tumoral/inmunología

RESUMEN

Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Asunto(s)

Glucólisis , Carcinoma de Células Escamosas de Cabeza y Cuello , Animales , Humanos , Ratones , Glucólisis/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/deficiencia , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Proteína BRCA2/deficiencia , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Regulación Neoplásica de la Expresión Génica , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Femenino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Regiones Promotoras Genéticas/genética , Proteína de la Leucemia Mieloide-Linfoide

RESUMEN

This article systematically reviewed the pathological features, molecular mechanisms, and tumor microenvironment of head and neck paraganglioma（HNPGL）, with a focus on pseudohypoxic HNPGL. It was demonstrated that pseudohypoxic HNPGL mainly involves multiple gene mutations, such as SDHx and VHL/EPAS1, which affect the stability and activity of HIF protein and exacerbate the development of the tumor. Meanwhile, the paper also analyzed the expression patterns of HIF-1α and HIF-2α in HNPGL, and found that differences in HIF activation may have an impact on the therapeutic response of specific subtypes. In addition, the paper explored the tumor microenvironment of HNPGL and found that immune cells such as macrophages, CD4⁺T cells, and CD8⁺T cells play an important role in the tumor, and the heterogeneity of the immune microenvironment also affects the choice of therapeutic approaches and responsiveness. Through comprehensive analysis, these findings not only contribute to a deeper understanding of the pathogenesis and developmental process of HNPGL, but also provide clues for future personalized treatments for specific subtypes.

Asunto(s)

Neoplasias de Cabeza y Cuello , Subunidad alfa del Factor 1 Inducible por Hipoxia , Paraganglioma , Microambiente Tumoral , Humanos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mutación , Paraganglioma/genética , Paraganglioma/inmunología , Paraganglioma/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética

RESUMEN

Head and neck malignancies are a significant global health concern, with head and neck squamous cell carcinoma (HNSCC) being the sixth most common cancer worldwide accounting for > 90% of cases. In recent years, there has been growing recognition of the potential role of alternative splicing (AS) in the etiology of cancer. Increasing evidence suggests that AS is associated with various aspects of cancer progression, including tumor occurrence, invasion, metastasis, and drug resistance. Additionally, AS is involved in shaping the tumor microenvironment, which plays a crucial role in tumor development and response to therapy. AS can influence the expression of factors involved in angiogenesis, immune response, and extracellular matrix remodeling, all of which contribute to the formation of a supportive microenvironment for tumor growth. Exploring the mechanism of AS events in HNSCC could provide insights into the development and progression of this cancer, as well as its interaction with the tumor microenvironment. Understanding how AS contributes to the molecular changes in HNSCC cells and influences the tumor microenvironment could lead to the identification of new therapeutic targets. Targeted chemotherapy and immunotherapy strategies tailored to the specific AS patterns in HNSCC could potentially improve treatment outcomes and reduce side effects. This review explores the concept, types, processes, and technological advancements of AS, focusing on its role in the initiation, progression, treatment, and prognosis of HNSCC.

Asunto(s)

Empalme Alternativo , Carcinoma de Células Escamosas de Cabeza y Cuello , Microambiente Tumoral , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Microambiente Tumoral/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética

RESUMEN

Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers. Preclinical studies and mouse models suggest that therapies targeting CD276 may outperform PD1/PD-L1 blockade. However, data from mouse models indicate a significant non-responsive population to anti-CD276 treatment, with the mechanisms of resistance still unclear. In this study, we evaluate the activity of anti-CD276 antibodies in a chemically-induced murine model of head and neck squamous cell carcinoma. Using models of induced and orthotopic carcinogenesis, we identify ITGB6 as a key gene mediating differential responses to anti-CD276 treatment. Through single-cell RNA sequencing and gene-knockout mouse models, we find that ITGB6 regulates the expression of the tumor-associated chemokine CX3CL1, which recruits and activates PF4+ macrophages that express high levels of CX3CR1. Inhibition of the CX3CL1-CX3CR1 axis suppresses the infiltration and secretion of CXCL16 by PF4+ macrophages, thereby reinvigorating cytotoxic CXCR6+ CD8+ T cells and enhancing sensitivity to anti-CD276 treatment. Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment.

Asunto(s)

Antígenos B7 , Neoplasias de Cabeza y Cuello , Ratones Noqueados , Animales , Ratones , Antígenos B7/metabolismo , Antígenos B7/genética , Antígenos B7/antagonistas & inhibidores , Humanos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Receptor 1 de Quimiocinas CX3C/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Línea Celular Tumoral , Ratones Endogámicos C57BL , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Modelos Animales de Enfermedad , Femenino , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos