Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A ...pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
Objectives/Hypothesis
To assess the causative factors that contribute to racial disparities in head and neck squamous cell carcinoma (HNSCC) and establish the role of hospital factors in racial ...disparities.
Study Design
Retrospective database analysis.
Methods
Patients with surgically treated HNSCC were identified using the National Cancer Database (2004–2014). Logistic and proportional‐hazard regression models were used to characterize the factors that contribute to racial disparities. Differences in quality of care received were compared among black and white patients using previously validated metrics.
Results
We identified 69,186 eligible patients. Black patients had a 48% higher mortality than white patients (HR 1.48; 95% confidence interval CI, 1.41–1.54). Black patients had a lower mean quality score (67.6%; 95% CI, 66.8%–69.4%) compared with white patients (71.2%: 95% CI, 71.0%–71.4%) for five quality metrics. After adjusting for differences in patient, oncologic, and hospital factors we were able to explain 60% of the excess mortality for black patients. Oncologic factors at presentation accounted for 57.7% of observed mortality differences, whereas hospital characteristics and quality of care accounted for 11.5%. After adjusting for these factors, black patients still had a 19% higher mortality (HR 1.19; 95% CI, 1.14–1.24).
Conclusions
Oncologic factors at presentation are a major contributor to racial disparities in outcomes for HNSCC. Hospital factors, such as quality, volume, and safety‐net status, constitute a minor factor in the mortality difference. Resolving existing disparities will require detecting head and neck cancer at an earlier stage and improving the quality of care for black patients.
Level of Evidence
3. Laryngoscope, 131:1053–1059, 2021
The Mu‐opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and metastasis in lung cancer cell ...lines. The effect of MNTX on other cell lines such as head and neck squamous cell carcinoma (HNSCC) has not been investigated. We measured the expression and activity of the receptor in different HNSCC cell lines. Then, we evaluated the impact of modulating the expression MOR and the effect of MNTX on the proliferation, clonogenic activity, invasion, and migration of two HNSCC (FaDu and MDA686Tu) cell lines expressing MOR and one cell line (UMSCC47) not expressing the receptor. We also evaluated the impact of MNTX on tumor growth and metastasis formation in vivo. Activation of the receptor with d‐Ala2,N‐Me‐Phe4, Gly5‐ol (DAMGO) caused a significant reduction in cyclic adenosine monophosphate levels in FaDu cells. Knockdown of MOR inhibited in vitro aggressive cell behaviors on FaDu and MDA686Tu cells and correlated with a reduction in markers of epithelial–mesenchymal transition. In vitro studies showed that MNTX strongly inhibited the proliferation, clonogenic activity, invasion, and migration of FaDu and MDA686Tu cells but has no effect on UMSCC47 cells. In vivo experiments demonstrated that MNTX suppresses tumor growth in HNSCC cell tumor‐bearing mice. Our studies indicate that MOR could be considered as a therapeutic target to treat HNSCC.
Low concentrations of methylnaltrexone (MNTX) inhibits cancer cell proliferation, migration, and epithelial–mesenchymal transition of head and neck squamous cell carcinoma (HNSCC) via snail in vitro and in vivo. Targeting mu‐opioid receptor (MOR‐1) in patients with HNSCC could be used as an adjuvant treatment strategy.
Therapeutic innovation for human papilloma virus‐related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. ...Our study establishes the first well‐characterized panel of patient‐derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype‐phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster‐growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV− patients that was prognostic in HPV− cases. In addition, reduced E7 and p16INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development.
What's new?
While the incidence of human papillomavirus (HPV)‐related head and neck squamous cell carcinoma (HNSCC) is increasing, therapeutic development has been slow to progress, due in part to insufficient biomarkers and lack of experimental models. Here, the authors present detailed characterization of HPV‐positive patient‐derived xenograft (PDX) and organoid models generated from HPV‐positive HNSCCs, which typically grow poorly outside the human body. The models retained genetic hallmarks frequently lost in HPV‐positive HNSCC cell lines. In addition, fast growing PDX and organoid models were found to harbor a high tumor mutational burden, which predicted tumor progression and survival when tested in patient cohorts.
It has been shown that those who have served in both combat missions and peacekeeping operations are at increased risk for Traumatic Brain Injury (TBI). Research suggests that this may result from ...their "wounds of war". Some wounds may be "invisible", such as depression, stress, and chronic pain, while others, such as physical disabilities, are more obvious. In February 2011, 35 scientists and representatives from NATO and Partner countries met in Vienna, Austria for a three-day NATO Advanced Research Workshop entitled "Wounds of War: Coping with Blast-Related Traumatic Brain Injury in Returning Troops". The aim of this publication, which presents papers from that workshop, is to critically assess the existing knowledge and to identify directions for future actions. The book addresses four key questions:1. Characterization of TBI: Which characteristics make up and help to classify TBI?2. Diagnosis and Assessment Issues Surrounding TBI: Which methods are used to diagnose and assess TBI? 3. Treatment of TBI: What are the latest treatment and therapy opportunities for soldiers after they have been diagnosed with TBI? 4. Quality of Life: How are the lives of TBI patients affected and in what ways can their quality of life be increased?.
Over the past 10 years, cancer immunotherapy has made significant progress in multiple cancer types and has been gradually been applied to clinical cancer care, in which the programmed cell death ...protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is one of the most attractive targets. Compared with traditional therapies, the emerging PD-1/PD-L1 blockade immunotherapy exhibited more satisfactory curative effects and lower toxicity for patients with advanced head and neck squamous cell carcinoma (HNSCC). This review analyzes the expression characteristics and clinical significance of PD-1/PD-L1 in HNSCC, the immunosuppressive roles of tumor cell and stromal cell expressing PD-1/PD-L1 in this disease, and presents the development landscape of PD-1/PD-L1 inhibitors, which may provide new curative alternatives for recurrent or metastatic HNSCC.
Poor survival of patients with locally advanced head and neck squamous cell carcinoma (LA‐HNSCC) is partly due to early diagnosis difficulties and the lack of reliable biomarkers for predicting ...treatment outcomes. In the discovery cohort, plasma‐derived extracellular vesicles (EVs) from LA‐HNSCC patients (n = 48) and healthy volunteers (n = 12) were used for profiling for microRNA (miRNA) expression by NanoString analysis. Ten EV‐associated miRNAs were differentially expressed between LA‐HNSCC patients and healthy volunteers. Subsequently, the results were validated in the individual discovery and additional cases (HNSCC, n = 73; control, n = 20) by quantitative RT‐PCR. Among 10 EV‐miRNAs, four (miR‐27b‐3p, miR‐491‐5p, miR‐1910‐5p, and miR‐630) were significantly dysregulated in LA‐HNSCC patients (n = 73) compared with healthy volunteers (n = 20). The miRNA prediction models were developed to discriminate HNSCC patients from healthy volunteers. The model using miR‐491‐5p was selected as a diagnostic biomarker for LA‐HNSCC with a sensitivity and specificity of 46.6% and 100%, respectively (P < .001). The dynamic changes of miRNA model score (ΔmiRNAs) were determined using scores pre‐ and postdefinitive treatment to further investigate the prognostic value of miRNA prediction models. The univariate and multivariate analyses indicated that ΔmiR‐491‐5p was the most powerful and independent prognostic indicator for overall survival (hazard ratio HR 5.66, 95% confidence interval, 1.77‐18.01; P = .003) and disease‐free survival (HR 2.82, 95% CI, 1.13‐7.05; P = .027) of HNSCC patients. In summary, the miR‐491‐5p prediction model could serve as a blood‐based diagnostic marker for LA‐HNSCC. Moreover, ΔmiR‐491‐5p could be a potential monitoring prognostic marker to reflect the survival of HNSCC patients.
We developed a microRNA (miR)‐491‐5p prediction model as a blood‐based biomarker for diagnosis in head and neck squamous cell carcinoma (HNSCC). Importantly, the dynamic changes of the miR‐491‐5p prediction score (ΔmiR‐491‐5p) from pre‐ and posttreatment might be a potential prognostic biomarker for HNSCC, which could help identify HNSCC patients who will eventually show tumor recurrence.
The lncRNA LINC00460 plays crucial roles in several epithelial cancers, although its mechanisms of action differ greatly in different cellular contexts. In this study, we aimed to determine the ...potential clinical applications of LINC00460 and elucidate the mechanisms by which LINC00460 affects the development and progression of head and neck squamous cell carcinoma (HNSCC).
The biological functions of LINC00460 were assessed in several epithelial cancer cell lines. The subcellular localization of LINC00460 was evaluated by cell nuclear/cytoplasmic fractionation and fluorescence in situ hybridization. RNA pull-down assays, LS-MS/MS analysis, and RNA and chromatin immunoprecipitation assays were performed to identify the molecular mechanism by which LINC00460 promotes HNSCC progression. The clinical pathological features of LINC00460 and PRDX1 were evaluated in HNSCC tissues and paired adjacent normal tissues.
LINC00460 enhanced HNSCC cell proliferation and metastasis in vitro and in vivo and induced epithelial-mesenchymal transition (EMT). LINC00460 primarily localized within the cytoplasm of HNSCC cells, physically interacted with PRDX1 and facilitated PRDX1 entry into the nucleus. PRDX1 promoted the transcription of LINC00460, forming a positive feedback loop. In addition, PRDX1 also promoted the transcription of EMT-related genes (such as ZEB1, ZEB2 and VIM) through enrichment on gene promoters in the nucleus. LINC00460 effectively induced HNSCC cell EMT in a PRDX1-dependent manner, and PRDX1 mainly mediated the EMT-promoting effect of LINC00460. High levels of LINC00460 and PRDX1 expression were positively associated with lymph metastasis, pathological differentiation and tumor size in HNSCC patients.
LINC00460 promoted EMT in HNSCC cells by facilitating PRDX1 entry into the nucleus. LINC00460 and PRDX1 are promising candidate prognostic predictors and potential targets for cancer therapy for HNSCC.
PDF
