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Skin cancer is the most common malignant disease in Caucasians.
The disease includes a diverse group of benign and malignant growth from different cell types, both cutaneous and extracutaneous, and that have different clinical outcomes. The most common types are basal cell carcinoma, squamous cell carcinoma and melanoma. The majority of skin cancer deaths result from melanoma. The most important etiological factors include UV light, ionizing radiation, and certain chemical carcinogens. Surgical removal is the primary means of treatment for most skin cancers. Other current treatments include chemotherapy, immunotherapy and targeted therapies.
May is Skin Cancer Awareness Month and with this collection of research in the field, the cancer team aim to increase knowledge of the disease and provide updates in melanoma/skin cancer prevention and detection.
Xeroderma pigmentosum (XP) is a rare genetic disorder that is associated with a higher risk of skin cancer. Here, the authors analyse the genomes of skin cancers from patients across five different XP groups, revealing genetic and molecular factors related to the mutational profile and UV-related mutagenesis in XP.
Genome sequencing has identified many recurrent mutations in melanoma. Here, we use targeted UV damage sequencing to show that many of these mutations are associated with UV damage hotspots that are linked to DNA binding by ETS transcription factors.
Circular RNAs are known to be linked to cancer regulation. Here, the authors identify a circular RNA signature associated with immune checkpoint response in melanoma.
Tumor microenvironment elements can influence tumor state, including in skin basal cell carcinomas. Here the authors show that spatially organized and self-propagating TREM2+ tumor associated macrophages promote Ly6D- tumor cell proliferation via secretion of oncostatin M.
IgE antibodies targeting cancer antigens can be used for immunotherapy. Here the authors present an IgE antibody targeting the melanoma-associated antigen, chondroitin sulphate proteoglycan 4, that recognises human melanoma, stimulates tumour cell cytotoxicity, and restricts tumour growth in humanised mouse models.
STING agonists have shown limited efficacy in early-phase clinical trials despite promising pre-clinical data. This study shows the potential clinical relevance of the use of combination STING agonists and demethylating agent therapies to induce the expression of STING.
Immunotherapy resistance is common among melanoma patients. Here, the authors identify three resistance mechanism subtypes across tumor-derived cell lines and matched samples and highlight antigen presentation disruption as a key mediator of resistance.
Melanocytes can de-differentiate into neural crest cell (NCC)- like states during metastatic melanoma progression. Here the authors compare DNA methylation profiles of NCCs and melanocytes, as well as primary and metastatic patient tissues and identify that DNA methylation changes of NR2F2 isoform 2 influence cell state transitions and melanoma metastatic spread.
TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.
IFN-Îł is associated with the efficacy of anti-tumour immune responses, and both pro- and anti-tumour functions have been ascribed to this cytokine. Here, the authors demonstrate that IFN-Îł signalling inhibits the maintenance of stem-like T cells, thereby impairing anti-tumour immune responses.
Cutaneous hyperpigmented lesions, including nevi, are populated by senescent melanocytes. Here the authors provide evidence for a novel strategy based on combining inhibition of the BCL-2 and MCL1 anti-apoptotic pathways that selectively eliminates senescent melanocytes in culture and in vivo.
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin cancers and have genetic overlap. Here, the authors use a multi-trait genetic and phenotypic analysis to reveal susceptibility loci for BCC and SCC, and report an optimised polygenic risk score for risk stratification.
Targeted therapeutic options for NRAS-mutant melanoma are limited. Here, the authors show that under metabolic stress NRAS-mutant melanoma cells activate a BRAF-dependent glycolysis pathway for survival, leading to improve efficacy of sorafenib when combined with glycolysis inhibitors.
Melanoma brain metastases (MBM) show heterogeneous therapeutic response determined by incompletely understood mechanisms. Here, the authors use a multi-OMICS approach and targeted sequencing (TargetSeq) to decipher programs that may define molecular subsets of MBM and their response to therapy.
Studying the cell composition of acral melanoma at the single-cell level could provide some clues about its poor response to immunotherapy. Here, the authors analyse acral and cutaneous melanoma patient samples using single-cell RNA-sequencing, and reveal a severe immunosuppressive state in acral melanomas
In patients with melanoma, increased RAS/mitogen-activated protein kinase (MAPK) pathway activity is known to drive chemotherapy resistance. Here, the authors identify CDK12 as a downstream effector of the RAS/MAPK pathway and therapeutic target which mediates chemotherapy resistance through increased expression of DNA repair associated genes.
Previous studies have characterized the diversity and dynamics of the T cell receptor (TCR) repertoire in patients with solid cancer. Here, by analyzing TCR repertoire data from multiple datasets, the authors report that melanoma-associated antigen-specific TCRs can be used to separate metastatic melanoma patients from healthy controls and to follow anti-tumor responses in patients treated with immunotherapy.
The metabolic environment of tumours has wide-ranging effects on the anti-tumour immune response and the outcome of immune therapy. Authors show here that the purine metabolite inosine enhances tumour immunogenicity and thus immune checkpoint blockade therapy response by inhibiting the ubiquitin-activating enzyme UBA6 in tumour cells.
Tumour mutational burden is a biomarker of immune checkpoint inhibitor response, but their association is not fully understood. Here, the authors train classifiers to identify key mutated processes which show stable predictive performance in multiple melanoma cohorts.
Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
The role of reciprocal tumour-stroma interactions in tumour invasion remains poorly characterised. Here, single-cell and spatial transcriptomics identifies the cell populations and their transcriptional reprogramming contributing to the spatial organization of the basal cell carcinoma invasive niche.
Whole-genome doubling (WGD) commonly occurs in many solid tumors. Here the authors use a zebrafish model of melanoma and in vitro models to show that BRAFV600E induces WGD via inhibition of RhoA and cytokinesis failure.
Lack of CD8+ T-cell infiltration into solid tumors is associated with poor responsiveness to immune checkpoint therapy (ICT). Here, the authors show that blocking the phosphorylation of HRS to reduce the induction of immunosuppressive exosomes promotes CD8+ T-cell infiltration into tumors and enhances the efficacy of ICT in mouse melanoma models.
The regulation of the distinct intrinsic phenotypic states in melanoma remain poorly characterised. Here, multi-omics analysis for a panel of 68 early passage melanoma cell lines reveals that cancer cell intrinsic transcriptomic programs are associated with distinct immune features.
Understanding CD8 + T cell response to immune checkpoint blockade at the molecular level is important for the design of more efficient cancer immune therapies. Authors show here that the histone lysine methyltransferase Suv39h1 controls the transcriptional programs that determine the functionality of CD8 + T cells and Suv39h1 inhibition may potentiate anti-PD-1 therapy of melanomas.
While cutaneous melanoma is linked to UV radiation, acral melanoma is not. Epigenetic mechanisms function as sensors to exposures and determinants of cell identity. Here, the authors use DNA methylation data to identify dysregulated pathways associated with UV radiation and pathobiology in cutaneous and acral melanomas.
Activating mutations of BRAF alone are inadequate to drive melanoma formation. Here the authors show that activation of Hippo signalling by oncogenic BRAF represents an additional safeguard to limit BRAF-dependent human melanocyte growth and melanoma formation.
The factors that determine the distinct profiles of NRAS mutants across different tumor types remain unclear. Here, the authors use an allelic series of conditional mouse models to investigate the molecular mechanisms underlying the enrichment of specific NRAS mutants in human melanoma
Slow-cycling melanoma persister cells are characterised by a high, reversible expression of H3K4 demethylase KDM5B. Here, the authors use genetic and chemical methods to enforce a permanent high expression of KDM5B and show that these cells transit to a melanocytic differentiated state and undergo cell cycle arrest.
Raster-Scanning-Optoacoustic Mesoscopy can be used to image the vasculature in skin cancer lesions but is limited by a long exposure time. Here; the authors increase the speed of the imaging using co-axial illumination and a high-sensitivity ultrasound detector path.
Acral melanoma affects the soles of the feet but the etiology is unknown. Here, the authors show that melanoma cells implanted into the foot pad of mice and exposed to mechanical stress show features of nuclear rupture, DNA damage, and Yap activation.
While mechanistic models play increasing roles in immuno-oncology, hand network curation is current practice. Here the authors use a Bayesian data-driven approach to infer how expression of a secreted oncogene alters the cellular landscape within the tumor.
STAG2 is a core subunit of the cohesin complex involved in DNA looping, but its transcriptional targets are largely unknown. Here the authors show STAG2 controls the 3D chromatin structure at the IRF9 locus to restrict IRF9 expression. Loss of STAG2 results in IRF9 activation, which in turn upregulates PD-L1 expression in cancer cells, suggesting a tumor suppressor function in immune evasion.
Loss-of-function CRISPR-based screens have identified several genes associated with cancer resistance to T cell-induced cytotoxicity. Here the authors perform a genome-scale, gain-of-function CRISPR screen and identify candidate genes, including the poly-N-acetyllactosamine synthase B3GNT2, whose overexpression confers tumor cell resistance to T cell cytotoxicity
Different adaptive mechanisms have been reported to reduce the efficacy of mutant BRAF inhibition in melanoma. Here, the authors show BRAF inhibition induces the translational regulation of metabolic genes leading to acquired therapy resistance.
Mechanisms underlying tumor cell plasticity remain poorly understood. Here, the authors show the presence of a dormant-invasive SOX10- subpopulation in cutaneous melanoma that can be targeted by cIAP1/2 inhibitors.
Despite acral melanoma being the most common melanoma subtype in non-White individuals, its molecular drivers remain unknown. Here, the authors integrate genomic and clinical data from 104 patients and identify late-arising focal amplifications of chr22q11.21 and LZTR1 as a key tumour promoter in this region.
Immunologically cold tumours don’t respond to immune checkpoint blockade inhibition due to poor recruitment of anti-tumour T cells. Authors show here that melanoma-associated lymphatic endothelial cells express G Protein-Coupled Receptor 182 that scavenges CXCL9 and other chemokines necessary for T cell recruitment.
Whether intermittent strategies of delivering drugs can improve cancer patients survival is still unclear. Here, the authors reports the results of a randomized phase II clinical trial aimed to compare the efficacy and safety of two dosing regimens (continuous and intermittent) of vemurafenib and cobimetinib combination as first-line treatment of patients with unresectable or metastatic advanced melanoma with BRAFV600 mutation
During tumor progression, cancer cells contact different neighboring cell types, but it is unclear how these interactions affect cancer cell behavior. Here, the authors use spatially resolved transcriptomics and single-cell RNA-seq to study the role of cilia at the tumormicroenvironment interface.
TGFβ is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGFβ is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGFβ dependent tumor growth.
Gene signatures that predict response to immune checkpoint blockade (ICB) therapies in melanoma have been based on preclinical models and pre-treatment samples. Here the authors develop pathway-based signatures to predict ICB response in melanoma using on-treatment samples, leading to improved performance.
The acidic tumour microenvironment in melanoma drives immune evasion by cAMP in tumor-infiltrating monocytes. Here, the authors show that the release of an adenylate cyclase inhibitor from micelles restores antitumor immunity and, when combined with regulatory T cell depletion, leads to remission of established B16-F10-OVA tumors.
The molecular underpinnings driving uveal melanoma (UM) progression are unknown. Here the authors show that loss of Polycomb Repressive Complex 1 triggers chromosomal instability, which promotes inflammatory signaling and migration in UM.
Lymphodepleting preconditioning is generally required prior to adoptive T cell therapy (ACT). Here the authors show in a preclinical melanoma model that anti-CD4 treatment as a post-conditioning regimen enhances the anti-tumor efficacy of ACT by promoting the expansion of IL-18Rαhi CD8+ T cells.
The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival.
Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.
Lymphocytic choriomeningitis virus (LCMV)-based viral vectors have been shown to induce potent antitumor immune responses. Here the authors show that a LCMV-based vaccine vector remodels the tumor-associated fibroblastic stroma, sustaining CD8+ T cell activation and reducing tumor growth in a preclinical model of melanoma.
Genomic studies of canine tumours have been done for individual cancer types or dog breeds. Here the authors analyse canine tumour genomics data across multiple breeds and cancer types, finding that mutational burden is associated with TP53 mutations and that Golden Retrievers are enriched for particular signatures.