Amaya Viros

Squamous cell carcinomas (SCCs) originate in epithelial tissues of older individuals who have been exposed to environmental carcinogens. Despite overlapping clinical hallmarks, SCCs from different anatomic sites have different prognoses. Here we show that fibroblasts confer site-specific cues that determine SCC proliferation and invasion. Oral and lung fibroblasts have distinct lipid metabolism, transferring unique lipids to SCC cells that promote epithelial-to-mesenchymal transition, and oral and lung SCC invasion. Whereas oral fibroblasts transfer sphingomyelins, which activate the ceramide–sphingosine-1-phosphate–STAT3 pathway and promote oral SCC invasion, lung fibroblasts transfer triglycerides to lung SCCs, thereby triggering cholesterol synthesis and invasion, which is associated with poor survival. By contrast, dermal fibroblasts are lipid poor, and cutaneous SCC is less invasive. Our data indicate that targeting fibroblast lipid synthesis and SCC lipid uptake or breakdown inhibits oral and lung epithelial cancer invasion.

Tumour-induced mechanisms of immune evasion hinder immune response to cancer, particularly in melanoma. mRNA translation, by ensuring accurate protein synthesis, regulates cancer phenotypes and immune response, but the underlying mechanisms remain unclear. Here, we reveal how O-sialoglycoprotein endopeptidase (OSGEP), catalysing the tRNA modification N ⁶ -threonylcarbamoyladenosine (t ⁶ A), drives protein homeostasis in cancer cells to maintain T-cell exclusion and prevent anti-tumour immune response. t ⁶ A-deficient melanoma cells disrupt efficient cytoplasmic translation of ANN codons (trinucleotides with A in the first position and N = any nucleotide), causing specific protein aggregation and the formation of integrated stress response-dependent stress granules. We discovered that OSGEP loss triggers melanoma regression by relocating RIG-I to stress granules, leading to its pathway activation. As a result, T-cells are recruited to the tumour site and orchestrate an anti-tumour immune response. Finally, an OSGEP-driven gene signature in melanoma patients is associated with T-cell infiltration and improved overall survival. Together, our findings position t ⁶ A tRNA modification as a promising therapeutic target for melanoma treatment.

Background: Primary care practitioners (PCPS) act as gatekeepers to specialists in cancer diagnosis. International cancer survival disparities are associated with stage of disease at diagnosis; therefore, early referral is crucial. Melanoma and keratinocyte cancers are the largest contributors to skin cancer deaths. Transformative education in skin lesions for PCPS provides opportunity to improve cancer outcomes. Methods: A systems-based model for Continuing Medical Education (CME): IMPACT, was delivered across 71 practices serving 480,855 individuals in Northwest England. Health utilisation outcomes (cancer conversion rates (CCR), chemoprevention prescriptions and cost benefits) and PCPs practice (post programme reflection on lesion consultations) data were analysed to measure effectiveness. Findings: One PCP from 35 general practices completed the IMPACT programme with 36 nonparticipant practices. The CCR was significantly increased in IMPACT group (7·09% to 7·78%) compared to the control (5·08% to 4·67%; difference between groups χ²(1) = 4·01, p = 0·045). The odds of detecting cancer in the IMPACT group were 1.72 times higher than in the control group (95% confidence interval 1·04–2·86), reducing the cost of diagnosing true skin cancer from £1,763 to £1,610 per case. The IMPACT programme also increased chemoprevention (5-Fluorouracil) prescriptions (fold change increase: 1·161835749, Z score value -7·7933, p <0·00001), and decreased prescriptions of less effective topical NSAIDs (fold change reduction: 0·580851064, Z score value 7·7933, p value <0·00001), resulting in a cost saving of £5041·08. There was no significant change in control group prescription rates resulting in an increased expenditure of £3929·46. Reflections from 70 post programme consultations demonstrated that health outcomes were driven by changes in PCP behaviour at individual and practice level.Interpretation: The IMPACT CME model results in transformative clinical practice: improving skin cancer diagnosis, chemoprevention and reducing healthcare costs. This provides a blueprint for other cancer types to improve survival.

Background: Ultraviolet radiation (UVR) affects local cutaneous and systemic immunity acutely. The wavelength, pattern and intensity of UVR exposure, individual skin phototype and immune state of individuals modulate the impact of UVR systemically. Local cutaneous immunity after UVR leads to immunosuppression that impacts melanoma. However, the effects of systemic UVR-induced changes on solid cancer therapy are not known. Methods: We investigated the impact of repeated UVR exposure on systemic immunity and immune checkpoint blockade (ICB) tumor responses in colorectal cancer and melanoma mouse models. Results: Animals exposed to chronic UVR exhibit decreased ICB response, which is mediated by systemic factors. Repeated UVR exposure expanded systemic lymphocyte populations and contracted total systemic myeloid cells. Specifically, UVR expanded peripheral blood CD4 ⁺ regulatory T cells (Tregs), which in turn led to greater Treg infiltration and immunosuppression in colorectal and skin cancer, and colorectal ICB-resistant tumors expressed unique pathways of ICB resistance due to systemic UVR. The response to ICB was restored with systemic pharmacological depletion of Tregs. In preliminary human data, there is an association between the molecular evidence of repeated UVR exposure in dermal fibroblasts and higher systemic Tregs. Discussion: Our data indicate that patients with melanoma and other cancers on immunotherapy should avoid repeated sun exposure.

Melanoma is a potentially fatal cancer with rising incidence over the last 50 years, associated with enhanced sun exposure and ultraviolet radiation. Its incidence is highest in people of European descent and the ageing population. There are multiple clinical and epidemiological variables affecting melanoma incidence and mortality, such as sex, ethnicity, UV exposure, anatomic site, and age. Although survival has improved in recent years due to advances in targeted and immunotherapies, new understanding of melanoma biology and disease progression is vital to improving clinical outcomes. Efforts to develop three-dimensional human skin equivalent models using biofabrication techniques, such as bioprinting, promise to deliver a better understanding of the complexity of melanoma and associated risk factors. These 3D skin models can be used as a platform for patient specific models and testing therapeutics.

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.