OBJECTIVES:Laryngeal cancer incidence has risen globally, yet survival outcomes have shown limited improvement over recent decades. This study evaluated contemporary outcomes across multiple centres in Northern UK and examined stage- and treatment-specific survival. DESIGN:Multi-centre retrospective observational study. SETTING AND PARTICIPANTS:Data were collected for 2028 patients with biopsy-proven squamous cell carcinoma of the larynx treated with curative intent between 2015 and 2021 across six tertiary head and neck cancer centres (Newcastle, Glasgow, Liverpool, Sheffield, Leeds, and Middlesbrough). MAIN OUTCOME MEASURES:Overall survival (OS) and disease-specific survival (DSS) were estimated using Kaplan-Meier analysis and compared using log-rank testing. RESULTS:Median follow-up was 40 months (mean age 66.8 years; 81% male). Overall mortality was 41% and disease-specific mortality 20%. Five-year OS declined with advancing stage: 72.0% (T1), 54.5% (T2), 50.6% (T3), and 45.2% (T4). In unadjusted analyses, surgery in T1 disease was associated with higher survival (5-year DSS 93.6% vs. 88.5%), while in advanced disease chemoradiotherapy was associated with the highest DSS (5-year DSS 70.2%), although differences were not statistically significant. No significant differences in DSS were observed across year of diagnosis (2015-2021). CONCLUSIONS:Survival outcomes for laryngeal cancer remain poor and have shown limited improvement over time. These findings provide important real-world insights into contemporary outcomes and highlight the need for earlier detection, prevention strategies, and prospective collaborative research to improve future outcomes.

Abstract Introduction and aims Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition caused by mutations in the gene for type VII collagen (C7). Loss of C7 leads to fragile skin that blisters and wounds easily and patients with severe forms of RDEB are at high risk of developing aggressive, and often fatal, cutaneous squamous cell carcinoma (cSCC). Currently, there are no approved treatments for RDEB-cSCC. This is due, in part, to an incomplete understanding of disease biology and potential therapeutic vulnerabilities and limited preclinical models of disease. To address this, we are integrating gene expression profiling data, identifying existing drugs that might be effective against RDEB-cSCC and developing xenograft models. Methods We screened 3135 US Food and Drug Administration (FDA)-approved drugs on patient-derived RDEB cancer cell lines (PDCLs) and performed an integrated analysis of RNA sequencing data. We have also developed four PDCL in vivo xenograft mouse models. Results Overall, 163 drugs were found to reduce cell growth by at least 30%. Analysis showed that several of these drugs targeted pathways involved in cancer growth and survival, such as phosphoinositide 3-kinase-Akt/mechanistic target of rapamycin, MEK/mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription, and histone deacetylase. In parallel, RNA sequencing revealed that these pathways were unusually active in patients’ tumours. Several of our lead candidate drugs that target these pathways were found to slow tumour cell growth and/or trigger cell death. We have developed four PDCL xenograft models that show different growth kinetics in vivo that can be used for further drug testing. Conclusions We have identified key pathways that are active in RDEB-cSCC, FDA approved drugs that target them and developed four PDCL xenograft models.

Abstract Introduction and aims Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers with metastatic potential. While only < 1 in 20 cSCCs may proceed to metastasize, when this occurs it is can be as lethal as most other metastatic cancers. Previous studies have shown that primary cSCCs harbour a high mutational burden, but it remains unclear whether genetic events determine metastatic potential. This study aimed to characterize the genetic evolution of cSCC metastasis from their corresponding primary tumours. Methods Overall, 488 formalin-fixed paraffin-embedded samples were collected from a retrospective cohort of immunocompetent patients with cSCC, including primary tumours, metastatic lesions and normal perilesional skin. Primary tumours were classified as nonmetastasizing if patients had ≥ 3 years of follow-up without metastasis. Dermatopathologist-annotated samples underwent whole-exome sequencing. Following quality control filtering, we carried out an in-depth analysis of 62 primary tumours that did not metastasize, 30 primary tumours that did metastasize and 26 metastases from patients with matched perilesional skin. Using bioinformatic pipelines, we determined mutational burdens, mutational signatures, significantly mutated genes, clonality and copy number alterations. Results We found that primary tumours that metastasized and metastases had the highest mutational burden and contained more subclones. Ultraviolet-driven signatures dominated all sample groups. dNdSCV analysis identified 10 significantly mutated genes with mutation of TP53 and HRAS among others enriched in metastasizing tumours and their metastases. Copy number variation analysis revealed a remarkable increase in genomic complexity in primary tumours that metastasized and in metastases. Conclusions Primary tumours that metastasize are genomically distinct from primary tumours that do not metastasize and harbour a massive burden of copy number alteration. Metastases share this burden and may become even more genetically complex. Enrichment of driver gene combinations coupled with genetic instability may confer tumours with metastatic potential.

BackgroundLaryngeal squamous cell cancer (LSCC) accounts for around one‐third of head and neck cancers, with smoking and alcohol as major risk factors. Despite advances in organ preservation, survival rates have stagnated globally over recent decades. The impact of socioeconomic deprivation on LSCC outcomes in the West of Scotland remains underexplored. We hypothesized that survival outcomes in the West of Scotland are poorer than cohorts from other developed nations.AimTo evaluate characteristics and survival outcomes for LSCC patients in the West of Scotland and identify predictors of survival.MethodsA retrospective cohort study of 867 LSCC patients in the West of Scotland (2014–2020) analyzed demographics, tumor staging, performance status, treatments, and socioeconomic status (Scottish Index of Multiple Deprivation, SIMD). Subgroup differences were assessed using chi‐squared tests. Survival analysis was performed with Kaplan–Meier curves, log‐rank tests, and Cox proportional hazards modeling.ResultsThe cohort had a male‐to‐female ratio of 3.2:1, with a mean age of 65.5 years, with 56% presenting with advanced disease. Most patients (70.7%) lived in the most deprived areas. Supraglottic cancers were the most common subsite (51%). Five‐year overall survival (OS) was 46%, with a median OS of 52 months. Glottic cancers had better outcomes (64% OS) compared to supraglottic cancers (36%). Predictors of survival included age, subsite, performance status, alcohol use, treatment modality, and deprivation.ConclusionLSCC survival in the West of Scotland is lower than in other European nations, influenced by advanced‐stage presentation, deprivation, and frailty. Addressing these factors is vital to improving outcomes.Level of evidence: III Laryngoscope, 2025

BACKGROUND:Cutaneous squamous cell carcinoma (cSCC) is a common cancer with a high morbidity rate and poor prognosis for metastatic disease. Disease may progress from premalignant actinic keratosis to invasive and metastatic cSCC, but it is perhaps best characterized as a disease continuum progressing from a differentiated to a progenitor-like state. The critical molecular mediators of this process remain poorly defined. Long noncoding (lnc)RNAs, a relatively unexplored class of RNA molecules > 200 nucleotides long, are likely to have important functional roles in cSCC. OBJECTIVES:To provide a comprehensive landscape of lncRNA expression during the cSCC continuum and to identify potentially functional lncRNA drivers of disease progression. METHODS:We interrogated bulk RNA sequencing (RNAseq) data from 110 patient samples, encompassing healthy sun-exposed skin (n = 26), actinic keratosis (n = 14), primary cSCC (n = 66) and metastases (n = 4), to identify changes in lncRNA expression during disease progression. We developed a bioinformatics pipeline to infer lncRNA function based on co-expression patterns and generated a lncRNA signature score, which we validated in head-and-neck squamous cell carcinoma (HNSC) and pancreatic adenocarcinoma (PAAD). We performed bulk RNAseq on 15 patient-derived cell lines and integrated these data to identify tumour cell-specific lncRNAs and validated our findings in multiple other cSCC gene expression cohorts. Using in vitro knockdown approaches we investigated the functional role of LINC00941. RESULTS:We found that lncRNA expression alone is sufficient to identify disease states and progression along the cSCC disease continuum. Correlation analysis revealed potentially functionally relevant lncRNAs and the processes they may regulate. We developed a 267 lncRNA signature that correlates with a progenitor-like state and predicts poor prognosis in HNSC and PAAD. Bulk RNAseq of patient-derived cell lines revealed tumour cell-specific lncRNAs, and knockdown of LINC00941 indicated that it is required for cell proliferation and colony formation in vitro. CONCLUSIONS:Our findings provide a comprehensive description of lncRNA transcriptomic changes in cSCC and demonstrate their functional relevance as biomarkers and drivers of disease progression in this and, potentially, other cancers.

Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential and development of metastases carries a poor prognosis. To address the need for reliable risk stratification, we developed cSCCNet, a deep learning model using digital pathology of primary cSCC to predict metastatic risk. A retrospective cohort of 227 primary cSCC from four centres is used for model development. cSCCNet automatically selects the tumour area in standard histopathological slides and then stratifies primary cSCC into high- vs. low-risk categories, with heatmaps indicating most predictive tiles contributing to explainability. On a 20% hold-out testing cohort, cSCCNet achieves an area under the curve (AUC) of 0.95 and 95% accuracy in predicting risk of metastasis, outperforming gene expression-based tools and clinicopathologic classifications. Multivariate analysis including common clinicopathologic classifications confirms cSCCNet as an independent predictor for metastasis, implying it identifies predictive features beyond known clinicopathologic risk factors. Histopathological analysis including multiplex immunohistochemistry suggests that tumour differentiation, acantholysis, desmoplasia, and the spatial localisation of lymphocytes relative to tumour tissue may be important in predicting risk of developing metastasis. Although further validation including prospective evaluation is required, cSCCNet has potential as a reliable and accurate tool for metastatic risk prediction that could be easily integrated into existing histopathology workflows.

TGM6 is a natural antagonist of mammalian TGF-β signaling produced by the murine helminth parasite Heligmosomoides polygyrus. It differs from the previously described agonist, TGM1 (TGF-β Mimic-1), in that it lacks domains 1/2 that bind TGFBR1. It nonetheless retains TGFBR2 binding through domain 3 and potently inhibits TGF-β signaling in fibroblasts and epithelial cells, but does not inhibit TGF-β signaling in T cells, consistent with divergent domains 4/5 and an altered co-receptor binding preference. The crystal structure of TGM6 bound to TGFBR2 reveals an interface remarkably similar to that of TGF-β with TGFBR2. Thus, TGM6 has adapted its structure to mimic TGF-β, while engaging a distinct co-receptor to direct antagonism to fibroblasts and epithelial cells. The co-expression of TGM6, along with immunosuppressive TGMs that activate the TGF-β pathway, may minimize fibrotic damage to the host as the parasite progresses through its life cycle from the intestinal lumen to submucosa and back again. The co-receptor-dependent targeting of TGFBR2 by the parasite provides a template for the development of therapies for targeting the cancer- and fibrosis-promoting activities of the TGF-βs in humans.

Oesophageal squamous cell carcinoma (ESCC) is associated with late-stage diagnosis, limited treatment options, the development of drug resistance and poor outcome. Epidermal growth factor receptor is frequently dysregulated in ESCC. EGFR copy number gain and/or protein overexpression are beneficial as predictive biomarkers for EGFR inhibitor therapy; however, inherent and acquired resistance limit response rates, and durable disease control is infrequent. This study investigates the causes of resistance to the off-patent EGFR inhibitor gefitinib in three gefitinib-resistance model systems: intrinsic, acquired resistance and growth factor (TGFβ)-induced resistance. Findings from studies in 13 ESCC cell lines were validated in tumour specimens from the GO2 clinical trial (n = 32), publicly available ESCC datasets (n = 264), cell line-derived xenograft (CDX) and patient-derived organoid (PDO) model systems. Gefitinib resistance in ESCC was associated with diverse mechanisms, including RTK signalling via PDGFRβ and IGFBP3/IGF1/IGF1R, as well as EMT, but was consistently associated with the maintenance of signalling via AKT across multiple cell lines and model systems. AKT or mTOR inhibitors synergised with gefitinib in 2D and anchorage-independent 3D assays. Gefitinib plus the AKT inhibitor capivasertib (Truqap™) was efficacious in human CDX and PDO models. Combining AKT/mTOR inhibitors with EGFR inhibitors in EGFR-driven ESCC shows synergism but with elevated toxicity. Monotherapy AKT/mTOR inhibitors or combined therapy at reduced doses could offer improved, cost-effective therapy options for gefitinib-resistant cancer.

Background:Laryngeal squamous cell cancer (LSCC) is a common head and neck cancer subtype, primarily linked to smoking and alcohol use. Despite declining incidence, survival outcomes have not improved. Prognostic scores, derived from blood-based markers like neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SIII), are increasingly recognized for their potential to predict survival outcomes and guide patient management. Methods:A retrospective analysis of 473 LSCC patients diagnosed in the West of Scotland (2014-2020) assessed the association of prognostic scores with overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Patients were categorized into high- and low-risk groups based on combined scores. Results:Low LMR and high-risk scores were significantly associated with worse OS, CSS, and RFS. Nodal status and disease stage remained strong predictors. Combining clinicopathological variables with prognostic scores improved survival prediction. Conclusion:Prognostic scores are valuable tools for survival prediction in LSCC and, when combined with clinicopathological factors, may guide patient management. Further validation is warranted.

BACKGROUND:Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. METHODS:The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. RESULTS:1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64). CONCLUSION:We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction.

Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (cSCC). Here we show in non-KS-associated patients that elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population. In contrast, we show that loss of Kindlin-1 leads to increased SCC tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. The metalloproteinase Mmp13 was upregulated in Kindlin-1-depleted tumors, and increased expression of MMP13 was responsible for driving increased invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth.

Abstract Background Increasing incidence of head and neck cancers (HNCs), driven by rising rates of oropharynx cancer (OPC), has been recorded around the world. This study examined trends in HNC and subsites (oral cavity, oropharynx, and larynx cancers) in Scotland focusing on assessing whether the sociodemographic profile has changed over the past 20 years. Methods Scottish Cancer Registry data (2001–2020) including European Age Standardised Rates of HNC and subsites were analysed in multivariate Poisson regression by age, sex, area-based socioeconomic status, and year of diagnosis (with interaction tests). Results Overall HNC and oral cavity cancer (OCC) incidence remained relatively stable. OPC incidence rates increased by 78%, while larynx cancer incidence declined by 27%. Over time, there were marginal shifts to a slightly older age profile for HNC (p = 0.001) and OCC (p = 0.001), but no changes in OPC (p = 0.86) and larynx cancer (p = 0.29). No shift in the sex profile of HNC was observed except for minor increases in female OCC rates (p = 0.001), and the socioeconomic distribution remained unchanged across all HNC subsites. Conclusions There have been no significant changes in the sociodemographic profile of HNC in Scotland over the last 20 years, despite the changing trends in HNCs with dramatically increasing incidence rates in OPC and reducing larynx cancer. This information can be used to target or stratify HNC prevention and control.

Journal Article Corrected proof Exon-specific oncogenic function of the long noncoding RNA plasmacytoma variant translocation 1 in cutaneous squamous cell carcinoma: a promising potential therapeutic target Get access Max Bone, Max Bone Writing - original draft, Writing - review & editing Cancer Research UK Scotland Institute and School of Cancer Sciences, University of Glasgow, Glasgow, UK Search for other works by this author on: Oxford Academic Google Scholar Gareth J Inman Gareth J Inman Writing - original draft, Writing - review & editing Cancer Research UK Scotland Institute and School of Cancer Sciences, University of Glasgow, Glasgow, UK Correspondence: Gareth Inman. Email: gareth.inman@glasgow.ac.uk https://orcid.org/0000-0002-6264-4253 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad476, https://doi.org/10.1093/bjd/ljad476 Published: 01 December 2023 Article history Received: 19 November 2023 Accepted: 23 November 2023 Published: 01 December 2023 Corrected and typeset: 23 January 2024

AbstractThe immunoregulatory cytokine TGF-β is pleiotropic due to the near-ubiquitous expression of the TGF-β receptors TβRI and TβRII on diverse cell types. The helminth parasite Heligmosomoides polygyrus has convergently evolved a family of TGF-β mimics (TGMs) that bind both these receptors through domains 1–3 of a 5-domain protein. One member of this family, TGM4, differs from TGF-β in acting in a cell-specific manner, failing to stimulate fibroblasts, but activating SMAD phosphorylation in macrophages. Primarily through domains 4 and 5, TGM4 interacts with multiple co-receptors, including CD44, CD49d (integrin α4) and CD206, and can up- and downmodulate macrophage responses to IL-4 and lipopolysaccharide (LPS), respectively. The dependence of TGM4 on combinatorial interactions with co-receptors is due to a moderated affinity for TβRII that is more than 100-fold lower than for TGF-β. Thus the parasite has elaborated TGF-β receptor interactions to establish cell specificity through combinatorial cis-signalling, an innovation absent from the mammalian cytokine.

Transforming Growth Factor-β (TGF-β) can have both tumour-promoting and tumour-suppressing activity in breast cancer. Elucidating the key downstream mediators of pro-tumorigenic TGF-β signalling in this context could potentially give rise to new therapeutic opportunities and/or identify biomarkers for anti-TGF-β directed therapy. Here, we identify C1orf106 (also known as innate immunity activator INAVA) as a novel TGF-β target gene which is induced in a SMAD3-dependent but SMAD2/SMAD4-independent manner in human and murine cell lines. C1orf106 expression positively correlates with tumourigenic or metastatic potential in human and murine breast cancer cell line models, respectively, and is required for enhanced migration and invasion in response to TGF-β stimulation. C1orf106 promoted self-renewal and colony formation in vitro and may promote tumour-initiating frequency in vivo. High C1orf106 mRNA expression correlates with markers of aggressiveness and poor prognosis in human breast cancer. Taken together, our findings indicate that C1orf106 may act as a tumour promoter in breast cancer.

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.

BACKGROUND:Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist that counter glioblastoma invasion. Here, we report that inhibition of ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking.METHODS:Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR overexpression using time-lapse microscopy, two orthotopic glioblastoma models, and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high-throughput, super-resolution and intravital imaging.RESULTS:High ATR expression was associated with significantly poorer survival in clinical datasets while histological, protein expression, and spatial transcriptomics using glioblastoma tumor specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed the invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalization of integrins at growth-cone-like structures, resulting in a tumor microtube retraction defect. The biological relevance and translational potential of these findings were confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging.CONCLUSIONS:We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far-reaching clinical benefits beyond radiosensitization.