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Melanoma and Skin Cancer Awareness Month

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.

Featured articles

Immune checkpoint inhibition (ICI) shows potential for cancer therapies, but response rates vary. Here, the authors use single-cell analyses to show that, in a 28 patient cohort, patients stratified by mucosal-associated invariant T (MAIT) percentages show different response rates, and ICI responders have more MAIT cells expressing CXCR4 and granzyme B.

Article | Open Access | | Nature Communications

Epigenetic mechanisms associated with the differentiation state of cancer cells and their heterogeneity influence tumor responses to oncogene-targeted therapies. In this study, the authors perform an epigenetic compound screen and single-cell analysis in BRAF-mutant melanoma cells to identify compounds that block three distinct drug-tolerant epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET proteins.

Article | Open Access | | Nature Communications

The identification of prognostic biomarkers can help stratify cancer patients. Here, the authors apply deep RNA sequencing from primary melanomas coupled with long-term clinical outcome data from a prospective multicentre phase III trial, to develop and validate a 121 metastasis-associated gene signature identifying early-stage melanoma patients at higher risk of metastasis and worse survival.

Article | Open Access | | Nature Communications

There is a clinical need to monitor immune-related toxicities of immune checkpoint blockade therapy. Here, the authors develop a digital SERS platform for multiplexed single cytokine counting to track immune-toxicities and demonstrate the ability to use pre-screening to identify patients at higher risk.

Article | Open Access | | Nature Communications

While genetic loci shared between cancer types have been identified, cross-cancer relationships for polygenic risk scores have not been well studied. Here, the authors have developed polygenic risk scores for 16 cancers in two large cohorts and identified positive and inverse cross-cancer associations.

Article | Open Access | | Nature Communications

Predicting who will develop skin cancer is difficult. Here, the authors from 23andMe developed a polygenic risk score for skin cancer based on a questionnaire and genetic data from more than 210,000 individuals and suggest that the score could be used in early screening programmes.

Article | Open Access | | Nature Communications

Inhibiting TGF-β1 to increase immune responses against tumors bears the risk of tumor-promoting toxicity. Here the authors show that selectively blocking TGF-β1 produced by immunosuppressive cells is feasible with anti-GARP:TGF-β1 antibodies and improves the efficacy of PD-1 blockade immunotherapy.

Article | Open Access | | Nature Communications

The circular RNA named ciRS-7 is overexpressed in human cancers, however, its spatial cellular expression patterns have not been explored. Here, the authors show that ciRS-7 is not expressed in colon cancer cells, but abundant in stromal cells within tumours, and that cancer-to-stromal cell ratios contribute to correlations between ciRS-7 and miR-7 target genes.

Article | Open Access | | Nature Communications

Tumor extracellular matrix has been associated with cancer progression, therapy resistance and immune suppression. Here, the authors show that collagen generates resistance to PD-1/PD-L1 immunotherapy by upregulating LAIR1 expression and downstream signaling, leading to increased CD8+ T cell exhaustion.

Article | Open Access | | Nature Communications

A significant proportion of patients develop innate or acquired resistance to immune checkpoint inhibitors. Here, the authors show that resistance to anti-PD-1 blockade is associated with TGF-beta driven major histocompatibility complex I (MHCI) down-regulation and a de-differentiated phenotype in melanoma patients.

Article | Open Access | | Nature Communications

Immunotherapies now dominate the treatment landscape for melanoma, but why they only work in a subset of patients remains unclear. Here, the authors perform an immunogenomic analysis on 67 intratumor sub-regions of a PD-1 inhibitor resistant melanoma, and 2 additional metastases from a single patient, mapping the spatial relationships between genomic and immune heterogeneity at high resolution.

Article | Open Access | | Nature Communications

The genetics of uveal melanoma has mainly been studied in primary tumours. In this study, the authors perform whole genome sequencing as well as immune cell profiling of biopsy samples obtained from metastatic uveal melanoma patients, providing an updated genomic landscape of these advanced lesions.

Article | Open Access | | Nature Communications

It is known that there are sex differences in the incidence and prognosis of certain cancers, including melanoma. In this study, the authors utilize a melanoma model to reveal that castrated mice have a higher metastatic burden associated with androgen dependent impaired neutrophil function.

Article | Open Access | | Nature Communications

Non-canonical HLA-bound peptides from presumed non-coding regions are potential targets for cancer immunotherapy, but their discovery remains challenging. Here, the authors integrate exome sequencing, transcriptomics, ribosome profiling, and immunopeptidomics to identify tumor-specific non-canonical HLA-bound peptides.

Article | Open Access | | Nature Communications

There are many patients who do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Here, the authors show a significant negative correlation between sphingosine kinase-1 (SK1) expression and survival for ICI-treated melanoma patients, and further show that targeting SK1 improves response to ICI in mouse cancer models.

Article | Open Access | | Nature Communications

Mucosal melanoma is a rare melanoma subtype that is poorly characterised. Here, the authors sequenced human, canine, and equine melanoma samples and performed a cross-species analysis, which revealed candidate driver genes, recurrent copy number alterations in regions syntenic between species, extensive intra-tumour heterogeneity and potential germline predisposing alleles

Article | Open Access | | Nature Communications

Prolyl hydroxylase domain protein 2 (PHD2) regulates cellular response to hypoxia. Here the authors show that PHD2 is downregulated in melanoma and that PHD2 depletion, in a mouse model, promotes the progression of benign melanocytic lesions into melanoma, via activation of the Akt/mTOR signaling cascade.

Article | Open Access | | Nature Communications

More featured articles

The ubiquitin ligase Siah2 has been implicated in immune responses. Here, the authors show that Siah2 null immune cells have an increased inflammatory response to inoculated melanoma cells, along with a reduced number of infiltrating immunosuppressive regulatory T cells, resulting in inhibition of tumour growth.

Article | Open Access | | Nature Communications

Aberrant glycosylation patterns on cancer cells promote several pro-tumorigenic functions, including enhancing tumor cell proliferation. Here the authors provide data that show melanoma cells downregulate GCNT2 with consequent loss of I-branched glycans; this leads to the formation of extended i-linear glycans and enhances melanoma growth via increases, in part, by IGF-1- and extracellular matrix-induced signaling.

Article | Open Access | | Nature Communications

BRAF or MEK1/2 inhibitors are cytostatic in melanoma and the surviving cells develop drug resistance. This study shows that the pro-survival pool is biased towards MCL1 in melanoma so that BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, improving tumour growth inhibition.

Article | Open Access | | Nature Communications

The response to immunotherapy of melanoma patients is heterogeneous. Here, the authors demonstrate that a high expression of the two major components of the immunoproteasome, PSMB8 and PSMB9, modulates the production of HLA peptides and it is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients.

Article | Open Access | | Nature Communications

Identification of clinical relevant biomarkers to predict response to immune checkpoint blockade (ICB) in melanoma remains challenging. Here, the authors show that stroma remodelling and reduced cell division are associated with durable response to anti-PD1 in a mouse model of melanoma and in ICB-treated patients.

Article | Open Access | | Nature Communications

Mucosal melanomas are challenging to treat partly because so little is known about the genetic drivers underpinning them. Here, the authors perform a genomic landscape analysis of samples collected from three continents, revealing a potential role for CDK4/6 or MEK inhibition in the treatment of the disease.

Article | Open Access | | Nature Communications

Resistance to BRAF inhibitors limits their clinical benefit in melanoma patients. Here, the authors show that the Aryl hydrocarbon Receptor (AhR) is a key mediator of resistant genes and use resveratrol, an AhR antagonist, to revert resistance in melanoma bearing mice.

Article | Open Access | | Nature Communications

As the overlap between heart disease and cancer patients increases as cancer-specific mortality is decreasing, identifying cancer patients who are at an increased risk of death from heart disease is important. Here the authors report on risk of death from heart diseases among more than 7.5 million cancer patients.

Article | Open Access | | Nature Communications

IFNγ secretion by CD8+T cells is critical for immunotherapy efficacy. In this study, the authors show that melanoma patients can become resistant to immunotherapy by acquiring chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2.

Article | Open Access | | Nature Communications

DNA mutations induced by dysregulated APOBEC3 expression are associated with tumour-progression and therapeutic resistance, but also with the generation of neoepitopes. Here, the authors show that APOBEC3 function can be exploited in a vaccine setting to generate heteroclitic neoepitopes, enhancing sensitivity to immunotherapy.

Article | Open Access | | Nature Communications

Adoptive T cell therapy (ACT) has yielded high response rates in melanoma, however 50–60% of patients experience no clinical benefit. Here, the authors identify predictive biomarkers, high non-synonymous mutation and high expressed neoantigen load, that associate with clinical benefit in ACT melanoma patients.

Article | Open Access | | Nature Communications

Phenotype switching is a form of plasticity that allows melanoma cancer cells that leave the primary tumour to invade secondary sites, to switch from an invasive to a proliferative state. Here the authors identify EDN3, and its synthetic enzyme ECE2, as a regulator of melanoma plasticity in the microenvironment.

Article | Open Access | | Nature Communications

Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.

Article | Open Access | | Nature Communications

Histology data exists for many cancer samples and the ability to automatically image this data may provide prognostic information. Here, the authors generated an algorithm to measure tumour infiltrating lymphocytes in melanoma histology specimens and show that the ratio of these immune cells to tumour cells has prognostic value.

Article | Open Access | | Nature Communications

As melanoma progresses, it evolves. Here, in advanced melanoma the authors study genomic evolution, highlighting trunk mutations dominated by the ultraviolet damage signature, common late truncal whole-genome duplication events, as well as selective copy number gain of mutant BRAF.

Article | Open Access | | Nature Communications

Many factors contribute to mutation hotspots in cancer cells. Here the authors map UV damage at single-nucleotide resolution across the human genome and find that binding sites of ETS transcription factors are especially prone to forming UV lesions, leading to mutation hotspots in melanoma.

Article | Open Access | | Nature Communications