Head And Neck Squamous Cell Carcinoma Research Articles

ATM is a Prognostic Biomarker of Survival in Head and Neck Squamous Cell Carcinoma Patients

This review examines the role of ATM expression in head and neck squamous cell carcinoma (HNSCC). Analysis revealed significant overexpression of ATM in HNSCC cells compared to normal control samples, suggesting its involvement in cancer proliferation. ATM expression was notably upregulated across various clinical parameters, including different stages of cancer, racial groups, genders, and age groups, highlighting its role in cancer progression. Validation using the GEPIA2 tool confirmed strong ATM expression throughout all four stages of HNSCC, with the highest levels in stage II and the lowest in stage I. Promoter methylation analysis of ATM showed distinct patterns across different demographics and cancer stages, reinforcing its significance. The study also explored the relationship between ATM expression and patient outcomes using the KM plotter tool, finding that high ATM expression was associated with better overall survival (OS), while low ATM expression correlated with better disease-free survival (DFS). Genetic mutation analysis via cBioPortal identified minimal ATM mutations in HNSCC, including in-frame, splice, truncating, and missense mutations, suggesting their role in ATM dysregulation. The STRING tool was used to construct a protein-protein interaction (PPI) network, revealing that the ATM gene interacts with ten key genes (NBN, ATR, CHEK2, MDC1, MSH2, MSH6, MRE11, TP53, TP53BP1, BRCA1), indicating its involvement in various biological functions. Functional annotation of differentially expressed genes (DEGs) through the DAVID web server revealed their participation in critical biological processes, including double-strand break repair, cellular response to DNA damage, and DNA damage checkpoints. KEGG pathway analysis further linked DEGs to cellular senescence, platinum drug resistance, homologous recombination, p53 signaling, and the cell cycle, underscoring ATM’s multifaceted role in 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.

Honokiol Is More Potent than Magnolol in Reducing Head and Neck Cancer Cell Growth.

The efficacy of treatment of head and neck squamous cell carcinoma (HNSCC) patients is still unsatisfactory, and there is an ongoing search for novel therapies. Locoregionally advanced HNSCC cases, which frequently require combined surgery and chemoradiotherapy, are especially difficult to treat. Natural compounds, like Magnolia-derived lignans-honokiol (HON) and magnolol (MAG)-can reduce cancer cell growth but retain a good safety profile and thus may show benefit as adjuvant therapeutics. The aim of this study was to evaluate the anti-cancer effects of HON and MAG in HNSCC cell lines and compare their effects between cisplatin-sensitive and cisplatin-tolerant cells. Cell viability was evaluated in FaDu and SCC-040 cells growing as monolayers and as spheroids. The effect of HON and MAG on the cell cycle, apoptosis, and gene expression was compared between wild-type FaDu cells and cisplatin persister FaDu cells. We observed that HON and MAG were more potent in reducing cell viability in cisplatin persister FaDu cells, although this effect was not directly followed by increased rates of apoptosis. Thus, HON's and MAG's capacity to affect cisplatin persister cells needs further studies. In general, we observed that HON exerted stronger cytotoxic effects than MAG in HNSCC cells, and the difference in their anti-cancer activity was especially pronounced in cells cultured in 3D.

The Role of Ryanodine Receptor 2 Polymorphisms in Oral Squamous Cell Carcinoma Susceptibility and Clinicopathological Features.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and oral squamous cell carcinoma (OSCC) is one of the most common types. There is strong evidence that ryanodine receptor 2 (RYR2) plays an important role in different types of cancer according to previous studies. Its expression is associated with survival in patients with HNSCC, but it is unknown whether altered RYR2 expression contributes to tumorigenesis. Therefore, we examined how RYR2 polymorphisms affect OSCC susceptibility and clinicopathological characteristics. Five single nucleotide polymorphisms (SNPs) of RYR2, rs12594, rs16835904, rs2779359, rs3765097, and rs3820216, were analyzed in 562 cases of OSCC and 332 healthy controls using real-time PCR. We demonstrated that RYR2 SNP rs12594 was significantly different between the case and control groups, but this difference was not significant after adjusting for personal habits. In contrast, we found that different genotypes of SNP rs2779359 were significantly associated with the characteristics of clinical stage and tumor size in OSCC patients, according to the odds ratios and the adjusted odds ratios; specifically, patients with the T genotype had 1.477-fold (95% CI, 1.043 to 2.091; p = 0.028) and 1.533-fold (95% CI, 1.087-2.162; p = 0.015) increases in clinical stage and tumor size, respectively, compared with patients with the C allele. The results of our study, in which RYR2 SNPs associated with OSCC progression and development were examined for the first time, suggest that clinicopathological characteristics may alter OSCC susceptibility. Finally, RYR2 SNP rs2779359 not only plays a role in both the prognosis and diagnosis of oral cancer but is also likely an important predictive factor for recurrence, response to treatment, and medication toxicity.

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.

PATH classification: a proposal for patients with HNSCC treated with salvage surgery

Abstract Purpose The aim of this study is to propose a classification for patients with recurrent head and neck squamous cell carcinoma (HNSCC) treated with salvage surgery based on the location of the primary tumor and data commonly found in the pathological report of the resection. Methods Retrospective study of 665 patients with HNSCC treated with a salvage surgery after a local and/or regional recurrence of the tumor. Results We propose a new postoperative classification for patients with recurrent HNSCC treated with salvage surgery. PATH classification stratifies patients into 4 stages based on the glottic or non-glottic location of the primary tumor, the local and regional pathologic extension of the tumor, the status of the surgical margins, and the presence of lymph node metastases with extracapsular spread. The PATH classification was more homogeneous in the prognosis of patients included in each of its stages, and it had a better prognostic discrimination capacity between stages than the rpTNM classification. According to the PATH classification, the 5-year disease-specific survival was: PATH I (n = 306) 82.8%; PATH II (n = 119) 47.1%; PATH III (n = 202) 24.4%; PATH IV (n = 38) 3.7%. For the rpTNM classification, the 5-year disease-specific survival was: stage I (n = 119) 85.1%; stage II (n = 134) 68.4%; stage III (n = 111) 59.5%; stage IV (n = 301) 33.3%. Conclusion The PATH classification for HNSCC patients with local and/or regional recurrence treated with salvage surgery had a better prognostic capacity than the rpTNM classification. Level of evidence Level IV.

Co-expression of miRNA players in advanced laryngeal carcinoma - Insights into the roles of miR-93-5p, miR-145-5p, and miR-210-3p.

Advanced laryngeal squamous cell carcinoma (LSCC) is the second most prevalent type of head and neck squamous cell carcinoma (HNSCC). Identifying microRNAs (miRNAs) related to key regulatory molecules or mechanisms could offer an alternative approach to developing new treatment strategies. The aim of our study is to evaluate significant correlations among deregulated miRNAs in advanced laryngeal carcinoma and to analyze, in silico, their strength of association, targets, and the most deregulated pathways. Several miRNAs demonstrated promising co-expression results, specifically miR-93-5p, miR-145-5p, and miR-210-3p. Their expressions were explored and further validated in a large set of in vivo advanced LSCC samples, which were subsequently used for bioinformatics and enrichment analyses. Our results highlight the significant roles of miR-93-5p, miR-145-5p, and miR-210-3p in regulating major pathways linked to the cell cycle via epithelial-to-mesenchymal transition (EMT), PI3K/Akt signaling, hypoxia, metabolism, apoptosis, angiogenesis, and metastasis. The associations between the expressions of these miRNAs and patients' clinical features could be central to the progression of advanced LSCC. Overall, our study provides important insights into the co-expression and regulatory networks of miR-93-5p, miR-145-5p, and miR-210-3p in advanced laryngeal carcinoma, underscoring their potential as therapeutic targets or biomarkers for this aggressive cancer. Further research is needed to elucidate the specific mechanisms through which these miRNAs contribute to the pathogenesis and progression of laryngeal carcinoma.

The Solute Carrier (SLC) Transporter Superfamily as Therapeutic Targets for the Treatment of Head and Neck Squamous Cell Carcinoma.

Background: Head and neck squamous cell carcinoma (HNSC) is the most prevalent cancer in the head and neck region, originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. The solute carrier (SLC) transporter superfamily, consisting of over 400 proteins across 65 families, plays a crucial role in cellular functions and presents promising targets in precision oncology. This study aims to analyze the expression of SLC transporters in HNSC and their potential as biomarkers and therapeutic targets. Methods: We leveraged mRNA and protein expression data from The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (HPA) to examine SLC transporter expression in HNSC. Gene Set Enrichment Analysis (GSEA) was conducted to assess the involvement of SLC transporters in various oncogenic pathways. Results: Significant upregulation of SLC transporters was observed in tumor tissues compared to normal tissues, with notable increases in SLC16A3, SLC53A1, SLC25A32, and SLC2A3. This upregulation correlated with poorer overall survival (OS) and disease-specific survival (DSS). GSEA revealed that these transporters are significantly involved in critical oncogenic pathways, including epithelial-mesenchymal transition (EMT), angiogenesis, and hypoxia, which are vital for cancer progression and metastasis. Conclusions: The study identifies SLC transporters as potential biomarkers and therapeutic targets in HNSC. Targeting these transporters with small molecule inhibitors could disrupt essential supply routes for cancer cells, enhancing treatment efficacy and improving patient outcomes. This study paves the way for developing SLC-based target therapies in precision oncology, with the goal of improving survival rates for patients with HNSC.

Abstract A094: Association between head and neck squamous cell carcinoma survival, tobacco use, and alcohol use, 2010-2021

Abstract The number of survivors of head and neck squamous cell carcinoma (HNSCC) in the United States is expected to rise in coming years due to higher quality and more accessible cancer care, diminished smoking and alcohol consumption rates, and increased frequency of less aggressive human papillomavirus (HPV)-associated oropharyngeal cancers. In developed nations, about 80% of HNSCC patients are current smokers, recent quitters (within the past year), and former smokers. About 39% of HNSCC patients living in the United States say that they are current drinkers, drinkers who exceed moderate levels, and binge drinkers. Of all HNSCC cases, between 72% and 80% are associated with specifically tobacco use, alcohol use, or the two. Tobacco use and alcohol consumption have been shown to be predictive for HNSCC diagnosis and survival. However, the underlying trends and social determinants linking HNSCC survival to tobacco use and alcohol consumption are poorly understood. To reach a better understanding, data will be sourced from the National Health Interview Survey from 2010 to 2021, adjusted for age and other confounders, and then analyzed with Cox proportional hazards regression analysis. The results will inform a deeper understanding of the connections between HNSCC survival and tobacco and alcohol use and can point to new approaches and treatment targets for patient care. Citation Format: Rashad Rahman, Meng Chen, Nosayaba Osazuwa-Peters. Association between head and neck squamous cell carcinoma survival, tobacco use, and alcohol use, 2010-2021 [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A094.

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.

Type 2-like polarization and elevated CXCL4 secretion of monocyte derived macrophages upon internalization of plasma-derived exosomes from head and neck cancer patients

BackgroundExosomes are closely associated with different aspects of tumor-progression in patients with head and neck squamous cell carcinoma (HNSCC), such as angiogenesis or immune regulation. As extracellular vesicles they are involved in the intercellular communication by transferring their cargo such as proteins and nucleic acids from one cell to another. However, the influence of tumor related plasma-derived exosomes on the polarization and characteristics of monocyte derived macrophages is not fully understood.MethodsExosomes were isolated from plasma samples of healthy donors (HD) and HNSCC patients and further evaluated with regard to morphology, size and protein composition via transmission electron microscopy, nanoparticle tracking, western blot analysis and cytokine assays. Differentiation and characteristics of monocyte derived macrophages upon exosome internalization were analyzed using flow cytometry and fluorescence microscopy. Macrophage cytokine secretion patterns were analyzed by human cytokine antibody arrays and ELISA measurements.ResultsOur data revealed elevated overall plasma levels of CTLA-4, PD-L1, and TIM-3 as well as elevated exosome-associated CTLA-4, PD-L2, TIM-3, and LAG-3 levels in HNSCC patients compared to HD. Furthermore, we observed a significant type 2-like polarization and elevated CXCL4 secretion of monocyte derived macrophages upon internalization of plasma-derived exosomes from HNSCC patients, which could be visualized by fluorescence microcopy of membrane stained exosomes.ConclusionsThe study provides new insights regarding exosome driven pro-tumorigenic immune regulation in the circulation of patients with head and neck cancer and could help to better understand the individual immunologic situation.

SFRP1 mediates cancer-associated fibroblasts to suppress cancer cell proliferation and migration in head and neck squamous cell carcinoma

BackgroundCancer-associated fibroblasts (CAFs), as key cell populations in the tumor microenvironment (TME), play a crucial role in tumor regulation. Previous studies on a prognostic signature of 8 CAF-related genes in head and neck squamous cell carcinoma (HNSCC) revealed that Secreted frizzled-related protein 1 (SFRP1) is one of the hub genes closely related to CAFs. SFRP1 is deficiently expressed in numerous types of cancer and is classified as a tumor suppressor gene. However, the role of SFRP1 in TME regulation in HNSCC remains unclear. This study aimed to explore the role of SFRP1 in the proliferation and migration of HNSCC cells by mediating CAFs and their regulatory mechanisms.MethodsThe expression differences, prognosis, and immune infiltration of SFRP1 in HNSCC were analyzed using the TIMER and GEPIA2 databases. The expression of SFRP1 in HNSCC tumor tissues, as well as the expression and secretion of SFRP1 in CAFs and tumor cells, were examined. An indirect co-culture system was constructed to detect the proliferation, migration, and apoptosis of HNSCC cells, and to clarify the effect of SFRP1 on tumor cells by mediating CAFs. Furthermore, the expression and secretion of 10 cytokines derived from CAFs that act on immune cells were verified.ResultsSFRP1 was differently expressed in HNSCC tumor tissues and highly expressed in CAFs. SFRP1 inhibited the proliferation and migration of tumor cells and promoted apoptosis by mediating CAFs. The detection of CAFs-derived factors suggested that the mechanism of action of SFRP1 was associated with the regulation of immune cells.ConclusionSFRP1 inhibits the proliferation and migration of HNSCC cells by mediating CAFs, and the mechanism of action is related to the regulation of immune cells, which may provide new research directions and therapeutic targets for HNSCC.

Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma

To enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HPV‐negative HNSCC patients who underwent RT. This ferroptosis‐related gene signature (FRGS) was a significant predictor of overall survival and recurrence‐free survival in HPV‐negative HNSCC patients who received RT. Subtype B of the FRGS, characterized by decreased expression of ferroptosis inducers [nuclear receptor coactivator 4 (NCOA4) and natural resistance‐associated macrophage protein 2 homolog/divalent metal transporter 1 (NRAMP2/DMT1)] and increased expression of suppressors [phospholipid hydroperoxide glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1)], was associated with poorer prognosis, potentially indicating the inhibition of ferroptosis. Furthermore, our in vitro and in vivo studies demonstrated that treatment with statins, such as atorvastatin and simvastatin, induced ferroptosis and sensitized radioresistant HNSCC cells to irradiation, improving radiosensitivity and potentially enhancing the response to RT. Additionally, in xenograft models, the combination of statins and RT led to a significant reduction in tumor initiation. These findings provide valuable insights for enhancing treatment and improving prognosis in HPV‐negative HNSCC by targeting ferroptosis and utilizing statins to sensitize tumors to RT‐induced cell death.

Increased Expression of PDGFA Is Associated With Poor Prognosis and Immune Infiltration in Head and Neck Squamous Cell Carcinoma.

Platelet-derived growth factor A (PDGFA) has been shown to be upregulated in several tumors, contributing to their malignant phenotypes. However, its expression and function in head and neck squamous cell carcinoma (HNSC) are not clearly understood. Thus, we aimed to evaluate this issue using bioinformatic analyses and primary experimental validation. The expression of PDGFA was analyzed using popular bio-databases and further validated by RT-PCR and immunohistochemical staining. Survival analyses were then performed. The association between PDGFA expression levels and immune cell infiltration in the immune microenvironment was assessed. PDGFA has been found to be significantly upregulated in a variety of cancers, including HNSC, and increased PDGFA expression may be an independent prognostic factor associated with immune cell infiltration in HNSC. Overexpression of PDGFA in HNSC is significantly associated with poor prognosis and immune cell infiltration in the tumor microenvironment (TME). PDGFA has potential as a molecular indicator for diagnosis, prognosis, and immune processes in HNSC.

CAF-secreted COL5A2 activates the PI3K/AKT pathway to mediate erlotinib resistance in head and neck squamous cell carcinoma.

To investigate the mechanisms behind acquired resistance to erlotinib in head and neck squamous cell carcinoma (HNSCC) with a focus on the role of cancer-associated fibroblasts (CAFs) and the PI3K/AKT signaling pathway. This study analyzed gene expression profiles of erlotinib-sensitive and -resistant HNSCC cell lines using datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. It included microarray and RNA-sequencing data, differentially expressed genes (DEGs) analysis, and pathway enrichment. Invitro experiments assessed the functional role of CAFs and the impact of the extracellular matrix component COL5A2 on erlotinib resistance. We identified 124 DEGs associated with erlotinib resistance, with key genes like COL5A2 significantly upregulated. CAFs were found to highly express COL5A2, enhancing erlotinib resistance by activating the PI3K/AKT pathway. Higher erlotinib resistance scores correlated with increased infiltration of CAFs. Erlotinib resistance in HNSCC is significantly influenced by the tumor microenvironment (TME), particularly through CAFs and the PI3K/AKT pathway. Targeting these mechanisms may offer new therapeutic strategies to overcome resistance in HNSCC patients.

Impact of kV-cone beam computed tomography dose on DNA repair mechanisms: A pilot study

PurposeIn head and neck squamous cell carcinoma (HNSCC), early complications of the radiotherapy (RT) are observed from the beginning of the treatment to a few months after its end. During external radiotherapy treatment, several patient-dependent parameters can cause a modification of the dose distribution compared to the planned distribution due to variation in patient positioning, anatomy, or intra-fractional movements for example. To verify these parameters during treatment sessions, one of the most commonly used solutions is the cone-beam computed tomography (CBCT). Nowadays, the use of CBCT may constitutes a significant part of the total dose at the end of treatment (up to 10 cGy per session) and more often the volume irradiated by imaging is larger than the one irradiated by the treatment, leading to unintentional irradiation of nearby organs.In this study, we asked whether the imaging low dose added to a following fraction dose (2Gy) may affect the biological response in terms of DNA repair. Material and methodsUsing an IVInomad dosimeter and scintillating fiber probes specially designed for this exploratory study, we exposed fibroblasts cells from head and neck cancer (HNC) patients to a CBCT dose followed by a radiotherapy fraction dose. DNA double strand breaks and DNA repair were assessed by immunofluorescence using the biomarkers gamma H2AX (γH2AX) and pATM. ResultsThe median dose of CBCT was measured between 17 to 21 mGy per session. The kinetics of both biomarkers were found to be strongly dependent on the individual factor in radiosensitive patients. For HNC patients, a prior CBCT dose applied few minutes before the 2Gy dose may have a sublinear effect on the DNA repair mechanisms and potentially on observed health tissue toxicity. ConclusionThe preliminary results obtained highlight the importance of individual and tissue factors for recognizing and repairing DSB during a treatment by radiotherapy using CBCT.

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.

Trem2-expressing multinucleated giant macrophages are a biomarker of good prognosis in head and neck squamous cell carcinoma.

Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk-management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC) - a type of macrophages - in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative-chemotherapy-treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the anti-tumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor associated macrophages, which co-localized in keratin tumor niches.

A bioengineered tumor matrix-based scaffold for the evaluation of melatonin efficacy on head and neck squamous cancer stem cells

Head and neck squamous cell carcinoma (HNSCC) presents a significant challenge worldwide due to its aggressiveness and high recurrence rates post-treatment, often linked to cancer stem cells (CSCs). Melatonin shows promise as a potent tumor suppressor; however, the effects of melatonin on CSCs remain unclear, and the development of models that closely resemble tumor heterogeneity could help to better understand the effects of this molecule. This study developed a tumor scaffold based on patient fibroblast-derived decellularized extracellular matrix that mimics the HNSCC microenvironment. Our study investigates the antitumoral effects of melatonin within this context. We validated its strong antiproliferative effect on HNSCC CSCs and the reduction of tumor invasion and migration markers, even in a strongly chemoprotective environment, as it is required to increase the minimum doses necessary to impact tumor viability compared to the non-scaffolded tumorspheres culture. Moreover, melatonin exhibited no cytotoxic effects on healthy cells co-cultured in the tumor hydrogel. This scaffold-based platform allows an in vitro study closer to HNSCC tumor reality, including CSCs, stromal component, and a biomimetic matrix, providing a new valuable research tool in precision oncology.

Identification of novel genetic variants associated with oral squamous cell carcinoma (OSCC) in South-West coast of India using targeted exome sequencing

Oral squamous cell carcinoma (OSCC) is a subset of head and neck squamous cell carcinoma (HNSCC). This study explores the genetic landscape of oral squamous cell carcinoma (OSCC) in a cohort of 33 patients from Southern India using targeted exome sequencing. Our analysis revealed a diverse range of mutations across the cohort, with missense mutations being the most prevalent. Pathogenic mutations, as classified by ClinVar, exhibited significant individual variation, highlighting the heterogeneity of OSCC. Seventy-five genes were identified to harbor pathogenic or potentially pathogenic mutations, with notable recurrence in genes such as TP53, PDGFRA, and RAD50 among others. Comparison with high-frequency mutation genes in HNSCC from TCGA database revealed significant overlap, emphasizing the relevance of these mutations across different populations. Additionally, several novel mutations were identified, including those in CHD8, ITPKB, and HNF1A, shedding light on potential genetic risk factors specific to this population. Functional annotation and pathway analysis underscored the involvement of these mutated genes in various cancer-related pathways. Despite limitations such as sample size and the need for further validation, this study contributes to a deeper understanding of OSCC pathogenesis and highlights potential genetic markers for prognosis and targeted interventions, especially in the Indian context.