Neck Squamous Cell Carcinoma Research Articles

Upregulation of LY6K induced by FTO-mediated demethylation promotes the tumorigenesis and metastasis of oral squamous cell carcinoma via CAV-1-mediated ERK1/2 signaling activation.

Lymphocyte antigen 6 complex locus K (LY6K) has been demonstrated to play a significant role in cancers and identified as a therapeutic biomarker for head and neck squamous cell carcinoma. However, the role of LY6K in oral squamous cell carcinoma (OSCC) has not been explored. The current study discovered that LY6K was aberrantly upregulated in OSCC cell lines and tissues and that high LY6K expression significantly correlated with poorer survival of OSCC patients. Through stable knockdown of LY6K, we found that the growth, colony formation, migration, and invasion of OSCC cells were substantially suppressed. In addition, tumor growth and lung metastasis in vivo were effectively inhibited by LY6K depletion. Mechanically, LY6K binds with CAV-1 and activates CAV-1-mediated MAPK/ERK signaling to exert its oncogenic effects on OSCC. In addition, LY6K expression in OSCC was discovered to be regulated by FTO-mediated RNA N6-methyladenosine (m6A) modification in an IGF2BP1-dependent manner. Generally, LY6K expression was upregulated by FTO-mediated demethylation in OSCC, which promoted the tumorigenesis and metastasis of OSCC via activating the CAV-1-mediated ERK1/2 signaling pathway.

MMP7, Regulated by c-Jun, is Involved in Oral Squamous Cell Carcinoma and Associated with Cancer-Related Fibroblasts Infiltration.

This study aimed to analyze the expression of Matrix Metalloproteinase 7 (MMP7) and molecular mechanism at the Transcription Factor (TF) level in Oral Squamous Cell Carcinoma (OSCC). MMP7 expression was preliminarily explored in Head and Neck Squamous Cell Car-cinoma (HNSCC) in the online database, followed by functional analysis and prediction of TF of MMP7. IHC was employed to detect MMP7 levels in OSCC samples. SCC9 and 293T cells were used to explore the transcriptional and regulatory effects of predicted TF on MMP7 by reporter double luciferase assay, RT-qPCR, western blotting, and cellular immunofluorescence. Transwell and TUNEL were employed to detect the migration and apoptosis. MMP7 was significantly up-regulated in HNSCC and OSCC tissues. Moreover, MMP7 was positively correlated with CAFs and significantly enriched in the signaling pathway of RNA degradation. The c-Jun pathway was also up-regulated in OSCC tissues, and predicted to be optimal TF of MMP7 with positive regulatory relationship. In OSCC, silencing and over-expression of c-Jun significantly decreased and increased the level of MMP7. Meanwhile, c-Jun affected the behavior of SCC9 cells, which showed that after c-Jun gene silencing, the ability of cell migration was weakened, while apoptosis was enhanced. When c-Jun gene was overexpressed, the migration ability was enhanced, but apoptosis was not significantly affected. MMP7 has been proven to be a key protein in the development of OSCC, and has the potential to become a biological marker and therapeutic target. It has been found that c-Jun could bind to the MMP7 promoter region, and the silencing or overexpression of c-Jun can positively regulate the expression of MMP7.

Neoadjuvant Chemotherapy for Borderline Resectable Head and Neck Cancers: A Comparative Study of Three-Drug and Two-Drug Regimens in a Low- and Middle-Income Country (LMIC) Context.

Background Borderline resectable head and neck squamous cell carcinoma (HNSCC) presents a significant therapeutic challenge, particularly in low- and middle-income countries (LMICs) like India. Neoadjuvant chemotherapy (NACT) aims to downstage tumors to achieve operability, but the optimal regimen remains controversial due to varying efficacy and toxicity profiles. This study compares the efficacy and toxicity of a three-drug regimen (TPF: docetaxel, cisplatin, and 5-fluorouracil) with a two-drug regimen (taxane and platinum) in patients with borderline resectable HNSCC in an LMIC setting. Methods In this retrospective cohort study, a total of 90 patients with borderline resectable HNSCC were included. Forty-three patients received the TPF regimen (Arm A), while 47 received the taxane + platinum regimen (Arm B). The outcomes measured included conversion to operability, stage-specific outcomes, overall survival (OS), progression-free survival (PFS), and treatment-related toxicity. Statistical analyses included chi-square tests for categorical variables, Kaplan-Meier survival analysis, and Cox proportional hazards modeling for multivariate analysis. Results The conversion to operability was significantly higher in the TPF group (72% vs. 51%, p=0.03). Patients in Arm A also exhibited a trend toward higher pathological complete response (pCR) rates compared to Arm B (60% vs. 43%, p=0.08). The overall survival and progression-free survival were improved in the TPF group, although the study did not reach statistical significance in these endpoints due to the limited sample size. However, the TPF regimen was associated with significantly higher toxicity. Grade 3-4 neutropenia occurred in 55% of the patients in Arm A compared to 32% in Arm B (p=0.01), and mucositis was observed in 47% of Arm A patients compared to 19% in Arm B (p=0.002). Febrile neutropenia was also more frequent in the TPF group (28% vs. 13%, p=0.04). Multivariate analysis identified the chemotherapy regimen (HR=1.45, 95% CI 1.05-2.01, p=0.02) and baseline nutritional status (HR=1.78, 95% CI 1.12-2.82, p=0.01) as independent predictors of overall survival. Conclusion While the TPF regimen offers superior efficacy in terms of tumor downstaging and conversion to operability, its higher toxicity profile limits its applicability in resource-constrained settings, such as LMICs. The taxane + platinum regimen, although less effective in downstaging, presents a more favorable toxicity profile, making it a viable alternative for patients with comorbidities or poor performance status. The choice between these regimens should be individualized, considering the patient's overall health, nutritional status, and the availability of supportive care. Further research is warranted to optimize NACT strategies for patients in LMICs.

Collagen prolyl 4-hydroxylase subunit α member-induced head and neck squamous cell carcinoma aggressiveness is antagonized by LLGL2 via reduced expression of occludin.

There are three isoforms of human collagen prolyl 4-hydroxylases (C-P4Hs), each of which has been reported to play an important role in regulating the progression of a variety of human cancers. By analyzing TGCA datasets on human head and neck squamous cell carcinoma (HNSC), we find that a higher expression of all three C-P4HAs (the α subunit of C-P4Hs) is a superior prognostic indicator than a higher expression of two or a single C-P4HA. Unexpectedly, some patients with higher levels of three C-P4HAs survive longer than patients whose tumors have lower expression of C-P4HAs. Therefore, there may be molecule(s) that can negate the deleterious effects of overexpressing C-P4HAs during cancer progression. By constructing a functional protein interaction network of C-P4HAs and analyzing molecules whose expressions are correlated significantly with that of C-P4HAs, we identify scribble cell polarity complex component 2 (LLGL2) as a factor that antagonizes the effects of overexpressed C-P4HAs on HNSC. Silencing of LLGL2 in the human oral squamous cell line Cal-27 upregulates the expression of occludin and increases cancer cell invasion and migration. In contrast, knocking down C-P4HA alone inhibits cell migration and invasion. Furthermore, simultaneously downregulating three C-P4HAs has more pronounced effects on inhibiting cell migration and invasion. Accordingly, high LLGL2 expression is also a marker indicating improved prognosis in patients with HNSC. These results suggest that the interplay between LLGL2 and C-P4HAs may be targeted to mitigate HNSC tumorigenesis and progression.

Inhibition of ATM or ATR in combination with hypo-fractionated radiotherapy leads to a different immunophenotype on transcript and protein level in HNSCC.

The treatment of head and neck tumors remains a challenge due to their reduced radiosensitivity. Small molecule kinase inhibitors (smKI) that inhibit the DNA damage response, may increase the radiosensitivity of tumor cells. However, little is known about how the immunophenotype of the tumor cells is modulated thereby. Therefore, we investigated whether the combination of ATM or ATR inhibitors with hypo-fractionated radiotherapy (RT) has a different impact on the expression of immune checkpoint markers (extrinsic), the release of cytokines or the transcriptome (intrinsic) of head and neck squamous cell carcinoma (HNSCC) cells. The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48h post-RT. Cell death was mainly induced by the combination of RT with both inhibitors, but stronger with ATRi. Further, the immune phenotype of cancer cells, not dying from combination therapy itself, is altered predominantly by RT+ATRi in an immune-stimulatory manner by the up-regulation of ICOS-L. However, the analysis of secreted cytokines after treatment of HNSCC cell lines revealed an ambivalent influence of both inhibitors, as we observed the intensified secretion of IL-6 and IL-8 after RT+ATRi. These findings were confirmed by RNAseq analysis and further the stronger immune-suppressive character of RT+ATMi was enlightened. We detected the down-regulation of a central protein of cytoplasmatic sensing pathways of nucleic acids, RIG-1, and found one immune-suppressive target, EDIL3, strongly up-regulated by RT+ATMi. Independent of a restrictive toxicity, the combination of RT + either ATMi or ATRi leads to comprehensive and immune-modulating alterations in HNSCC. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi.

485 - Prognosis prediction in head and neck squamous cell carcinoma by radiomics and clinical information

485 - Prognosis prediction in head and neck squamous cell carcinoma by radiomics and clinical information

Inhibition of PNCK inflames tumor microenvironment and sensitizes head and neck squamous cell carcinoma to immune checkpoint inhibitors

BackgroundThe landscape of the tumor microenvironment (TME) is intricately linked to the development of head and neck squamous cell carcinoma (HNSCC) and significantly influences immunotherapy efficacy. Recent research has underscored...

159 (PB147): Cancer associated fibroblasts are associated with NK cell exhaustion in Head and Neck Squamous Cell Carcinoma

159 (PB147): Cancer associated fibroblasts are associated with NK cell exhaustion in Head and Neck Squamous Cell Carcinoma

Exploring a specific type of tissue-resident natural killer cell involved in the anti-tumor and immunotherapy response in human papillomavirus-positive head and neck squamous cell carcinoma using scRNA-seq

Exploring a specific type of tissue-resident natural killer cell involved in the anti-tumor and immunotherapy response in human papillomavirus-positive head and neck squamous cell carcinoma using scRNA-seq

Keratin 17 and A2ML1 are negative prognostic biomarkers in non-small cell lung cancer

Although the overall prognosis for patients with non-small cell lung cancer (NSCLC) has improved over the past several decades, there are still survival differences that are not accurately defined by clinicopathological factors. Thus, there is an unmet clinical need to develop novel approaches to enhance prognostic accuracy for these patients. Keratin 17 (K17) is a negative prognostic biomarker in a wide range of cancer types, including pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, and pulmonary adenocarcinoma (LUAD), but has yet to be investigated as a prognostic biomarker in primary lung squamous cell carcinoma (LSCC). Based on TCGA RNA-seq data, alpha-2-macroglobulin like 1 (A2ML1), a protease inhibitor, is highly correlated with K17 in other solid tumors, including pancreatic ductal adenocarcinoma and is also a prognostic biomarker for LSCC, although the prognostic accuracy of A2ML1 for LUAD has not been tested. Thus, we hypothesized that A2ML1 expression correlates with K17 expression and that K17/A2ML1 co-testing could provide complementary prognostic data for NSCLC. The aims of this study were to explore K17 and A2ML1 as dual prognostic biomarkers, using publicly available gene expression databases [The Cancer Genome Atlas (TCGA)] LSCC (n=266), LUAD (n=271)] and multiplexed immunohistochemistry (mIHC) on representative sections of LSCC (n=104) and LUAD (n=107) from two major academic medical centers. Our results suggest that using either mRNA or mIHC-based methods, combined K17 and A2ML1 testing provides information, independent of other clinicopathologic variables, that could impact treatment decisions for patients with NSCLC.

Multiomic Characterization and Molecular Profiling of Nuclear Protein in Testis Carcinoma.

Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene NUTM1 on chromosome 15q14. Co-occurring alternations have not been fully characterized. We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris). While NC is driven by NUTM1 fusion oncoproteins, co-occurring DNA mutations in epigenetic or cell cycle pathways were observed in 26% of cases. There was no significant difference between the fusion partner of NUTM1 and co-occurring gene mutations. RNA sequencing analysis showed increased MYC pathway activity in NC compared with head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC), which is consistent with the known pathophysiology of NC. Characterization of the NC tumor microenvironment using RNA sequencing revealed significantly lower immune cell infiltration compared with HNSCC and LUSC. NC was 10× higher in patients with HNSCC and LUSC younger than 50 years than in those older than 70 years. To our knowledge, this is the first series of NC profiled broadly at the DNA and RNA level. We observed fewer intratumoral immune cells by RNA sequencing, which may be associated with anecdotal data of lack of immunotherapy benefit in NC. High MYC pathway activity in NC supports ongoing trials targeting MYC suppression. The incidence of NC among patients younger than 50 years with LUSC/HNSCC supports testing for NC in these patients. The prognosis of NCs remains dismal, and future studies should focus on improving the response to immunotherapy and targeting MYC.

P65-4 PembrolIzumab plus platinum and gemcitabine as first-line treatment of recurrent head and neck squamous cell carcinoma

P65-4 PembrolIzumab plus platinum and gemcitabine as first-line treatment of recurrent head and neck squamous cell carcinoma

Effect of plasma-induced oxidation on NK cell immune checkpoint ligands: A computational-experimental approach

Non-thermal plasma (NTP) shows promise as a potent anti-cancer therapy with both cytotoxic and immunomodulatory effects. In this study, we investigate the chemical and biological effects of NTP-induced oxidation on several key, determinant immune checkpoints of natural killer (NK) cell function. We used molecular dynamics (MD) and umbrella sampling simulations to investigate the effect of NTP-induced oxidative changes on the MHC-I complexes HLA-Cw4 and HLA-E. Our simulations indicate that these chemical alterations do not significantly affect the binding affinity of these markers to their corresponding NK cell receptor, which is supported with experimental read-outs of ligand expression on human head and neck squamous cell carcinoma cells after NTP application. Broadening our scope to other key ligands for NK cell reactivity, we demonstrate rapid reduction in CD155 and CD112, target ligands of the inhibitory TIGIT axis, and in immune checkpoint CD73 immediately after treatment. Besides these transient chemical alterations, the reactive species in NTP cause a cascade of downstream cellular reactions. This is underlined by the upregulation of the stress proteins MICA/B, potent ligands for NK cell activation, 24 h post treatment. Taken together, this work corroborates the immunomodulatory potential of NTP, and sheds light on the interaction mechanisms between NTP and cancer cells.

Impact of Dental Pulp Stem Cell Secretome on Apoptosis, Proliferation and Drug Resistance of Head and Neck Squamous Cell Carcinoma Cell Lines: In vitro study

Impact of Dental Pulp Stem Cell Secretome on Apoptosis, Proliferation and Drug Resistance of Head and Neck Squamous Cell Carcinoma Cell Lines: In vitro study

234 (PB222): Rational combination of pan-TEAD inhibitor SW-682 and MEK inhibitor mirdametinib in head and neck squamous cell carcinomas leads to synergistic response

234 (PB222): Rational combination of pan-TEAD inhibitor SW-682 and MEK inhibitor mirdametinib in head and neck squamous cell carcinomas leads to synergistic response

Clinicopathological Review of Head and Neck Squamous Cell Carcinomas After Neoadjuvant Chemotherapy.

The benefit of neoadjuvant chemotherapy (NAC) in the treatment of head and neck squamous cell carcinoma (HNSCC) remains unclear. We retrospectively collected 30 patients with HNSCC who had undergone radical resection after NAC. We pathologically evaluated the therapeutic response to NAC, and classified the residual tumor patterns. In addition, we compared the maximum horizontal diameter on pathology with imaging. The residual patterns were categorized as follows: 10 cases of shrunken type, 11 cases of mixed type, and seven cases of fragmented type. The majority of underestimation cases - those cases in which the maximum horizontal diameter measured on post-NAC imaging was less than the pathological size after resection - were multifocal residual lesions, with a tendency for more frequent "positive" or "close" surgical margins. The strategy of performing NAC to reduce resection volume is not appropriate, and resection margins should be based on the assessment before NAC.

Systemic Metabolic and Volumetric Assessment via Whole-Body [18F]FDG-PET/CT: Pancreas Size Predicts Cachexia in Head and Neck Squamous Cell Carcinoma.

Background/Objectives: Cancer-associated cachexia in head and neck squamous cell carcinoma (HNSCC) is challenging to diagnose due to its complex pathophysiology. This study aimed to identify metabolic biomarkers linked to cachexia and survival in HNSCC patients using [18F]FDG-PET/CT imaging and machine learning (ML) techniques. Methods: We retrospectively analyzed 253 HNSCC patients from Vienna General Hospital and the MD Anderson Cancer Center. Automated organ segmentation was employed to quantify metabolic and volumetric data from [18F]FDG-PET/CT scans across 29 tissues and organs. Patients were categorized into low weight loss (LoWL; grades 0-2) and high weight loss (HiWL; grades 3-4) groups, according to the weight loss grading system (WLGS). Machine learning models, combined with Cox regression, were used to identify survival predictors. Shapley additive explanation (SHAP) analysis was conducted to determine the significance of individual features. Results: The HiWL group exhibited increased glucose metabolism in skeletal muscle and adipose tissue (p = 0.01), while the LoWL group showed higher lung metabolism. The one-year survival rate was 84.1% in the LoWL group compared to 69.2% in the HiWL group (p < 0.01). Pancreatic volume emerged as a key biomarker associated with cachexia, with the ML model achieving an AUC of 0.79 (95% CI: 0.77-0.80) and an accuracy of 0.82 (95% CI: 0.81-0.83). Multivariate Cox regression confirmed pancreatic volume as an independent prognostic factor (HR: 0.66, 95% CI: 0.46-0.95; p < 0.05). Conclusions: The integration of metabolic and volumetric data provided a strong predictive model, highlighting pancreatic volume as a key imaging biomarker in the metabolic assessment of cachexia in HNSCC. This finding enhances our understanding and may improve prognostic evaluations and therapeutic strategies.

Apoptotic effect of betulinic acid in FaDu human head and neck squamous cell carcinomas

Apoptotic effect of betulinic acid in FaDu human head and neck squamous cell carcinomas

DEMOGRAPHIC PROFILE AND RISK FACTORS OF HEAD AND NECK SQUAMOUS CELL CARCINOMA IN NATIONAL ONCOLOGY CENTER IN ADEN, YEMEN: PROSPECTIVE CROSS-SECTIONAL STUDY

Head and neck squamous cell carcinoma (HNSCC) is a significant health concern in Yemen, with a notable impact on the population. Major risk factors for HNSCC in this region include qat chewing, cigarette smoking, and tobacco. The goal of our study was to analyze the correlation between demographic profiles, affected anatomical sites, and risk factors. A prospective cross-sectional study was conducted using data extracted from the medical records of patients diagnosed with HNSCC at the National Oncology Center (NOC) in Aden, Yemen, covering the period from January 2023 to December 2023. Information on patient demographics, primary tumor locations, family history, and exposure to risk factors such as qat chewing and cigarette smoking was collected through a structured questionnaire. The study included 100 patients, with a male-to-female ratio of 2.45:1. The mean age of the patients was 53.2 ± 14.7 years, with a significant portion (41%) falling in the 36–54 age group and (40%) falling in the 55–73 age group. The most commonly affected site was the nasopharynx, accounting for 48% of cases. Qat chewing was the predominant risk factor among patients (74%), followed by cigarette smoking (50%) and tobacco (28%). Middle-aged individuals, particularly men aged 36–54 and 55–73 years, are disproportionately affected by HNSCC in Yemen. The nasopharynx emerges as the most prevalent site of cancer. Qat chewing stands out as a prevalent risk factor among patients, followed by cigarette smoking and tobacco. Public education on the risk factors associated with HNSCC is essential for effective disease management and prevention efforts in Yemen.

Unveiling the Effects of Cruciferous Vegetable Intake on Different Cancers: A Systematic Review and Dose-Response Meta-analysis.

Epidemiological studies indicated that cruciferous vegetable intake is associated with positive health outcomes. However, the role of cruciferous vegetables may have differential impacts on various cancers. This meta-analysis aims to review recent epidemiological studies on the link between cruciferous vegetables and various cancers. It seeks to identify the optimal intake dose and timing of cruciferous vegetables influencing their association with cancer risk. Studies on cruciferous vegetables and cancer were searched in PubMed, NCBI, Web of Science, and Elsevier databases from 1978 to June 2023. Extracted data from 226 relevant case-control and cohort studies were expressed by standardized mean difference and 95% CI, followed by the subgroup analysis to eliminate heterogeneity. Intake of cruciferous vegetables can prevent cancers, with an odds ratio of 0.77 and risk ratio (RR) of 0.96. The intake levels of cruciferous vegetables associated with the risk of colorectal cancer, lung cancer, upper gastrointestinal cancer, gynecological cancer (ovarian cancer and endometrial cancer), bladder cancer, renal cancer, and prostate cancer were found to be 5.41 servings/week, 5.41 servings/week, 5.5 servings/week, 7.4 servings/week, 5.5 servings/week, 4.85 servings/week, and 3 servings/week, respectively. In a cohort followed for 2 to 15 years, limited consumption of cruciferous vegetables was correlated with a higher cancer RR. In the Asian population, cruciferous vegetables had a significant relationship with lung cancer, head and neck squamous cell carcinoma, and esophageal cancer. Conversely, cruciferous vegetables are predominantly associated with colorectal, renal, gynecological, and prostate cancer in the American population. This study highlights the complex link between cruciferous vegetables and cancer, influenced by factors such as cancer type, region, intake level, and follow-up duration.