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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

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

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

More featured articles

MAPK-targeted therapies fail to achieve complete remission. Here, the authors show that anti-apoptosis resistance is acquired in these targeted therapies through the mRNA destabilization of NOXA which leads to dependence on MCL-1, and that sequential combination of MCL-1 inhibition with targeted therapies overcomes this resistance.

Article | Open Access | | Nature Communications

The aggressive nature of melanoma cells relies on their ability to switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state; however, the mechanisms governing this switch are unclear. Here, using in vivo models of human melanoma, the authors show that CD271 is a key regulator of phenotype switching and metastasis formation.

Article | Open Access | | Nature Communications

In metastatic melanoma, ADAR1 is downregulated, facilitating proliferation. Here, the authors show an ADAR1-dependent and RNA-editing-independent regulation of melanoma invasion mediated by ITGB3 expression, which can be reversed when ITGB3 is blocked.

Article | Open Access | | Nature Communications

The relationship between autophagy and BRAF signalling is unclear. Here, the authors describe that BRAF inhibition induces the autophagy-lysosomal function in BRAF-mutant melanomas via modulation of the TFEB and ZKSCAN3 transcriptome, which downregulates TGF-β and suppresses melanoma progression.

Article | Open Access | | Nature Communications

In melanoma, reduced ADAR1 impairs A-to-I microRNA editing. Here, the authors show that miR-378a-3p undergoes this editing in non-metastatic cells and the edited form of miR-378a-3p binds to the PARVA oncogene, inhibiting its expression and preventing melanoma progression and metastasis.

Article | Open Access | | Nature Communications

The interaction of DOT1L with MLL oncogenic fusion proteins has been implicated in leukemogenesis. Here, the authors show a contrasting role for DOT1L in protecting UVR-induced melanomagenesis by facilitating DNA repair through interaction with XPC.

Article | Open Access | | Nature Communications

Melanoma persister cells are tolerant to anti-BRAF and anti-MEK inhibition and can trigger cancer relapse. Here the authors show that a subset of N6-methyladenosine modified mRNAs is translationally activated in persister cells. This preferential translation can be abrogated via eIF4A inhibition.

Article | Open Access | | Nature Communications

Exosomes are extracellular vesicles that can favor tumor development and metastasis. Here, the authors show that cancer exosomes may also exert a suppressive function; in fact, exosomes from non-metastatic melanoma cells can lead to the recruitment of patrolling monocytes, which clear cancer cells at the pre-metastatic niche.

Article | Open Access | | Nature Communications

The melanoma-driver mutations in NRAS and BRAF are mutually exclusive but the contribution of RAF signalling downstream of NRAS remains to be clarified. Here, using mouse models, the authors show specific roles of each member of the RAF family at different stages of melanomagenesis.

Article | Open Access | | Nature Communications

Usp9x is a deubiquitinating enzyme with altered expression in melanoma; however its functional contribution in this context is not clear. Here the authors show that Usp9x regulates the stability of the transcription factor Ets-1 that in turn impacts metastatic melanoma through increased expression of NRAS.

Article | Open Access | | Nature Communications

Melanocytic nevus count is associated with melanoma risk. In this study, a meta-analysis of 11 nevus GWAS studies identifies novel SNPs in KITLG and 9q32, and bivariate analysis with melanoma GWAS meta-analysis reveals that most nevus genes affect melanoma risk, while melanoma risk loci do not alter the nevus count.

Article | Open Access | | Nature Communications

Immunotherapy can induce antigen spreading of antitumor T cell response, which correlates with better outcomes. Here the authors show that tissue-resident memory CD8 T cells promote antigen spreading via lysing tumor cells and promoting their uptake and cross-presentation by dendritic cells, thereby eliciting de novo T cell responses.

Article | Open Access | | Nature Communications

The epigenetic mechanisms of melanoma drug resistance are poorly understood. Here, the authors develop a CRISPR-Cas9 screen targeting epigenetic regulators and discover that SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling.

Article | Open Access | | Nature Communications

CCL5 is an important chemokine for modulation of inflammatory responses, but how CCL5 expression is regulated is still unclear. Here the authors show that the CCL5 locus contains two enhancers, with the proximal enhancer being responsible for homeostatic expression and the distal enhancer enforcing inducibility, while both enhancers are modulated by RUNX3.

Article | Open Access | | Nature Communications

Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8+ T cell responses that result in potent tumor suppression.

Article | Open Access | | Nature Communications

Each cell type in the tumour microenvironment has unique metabolic demands enabling specific functions. Here the authors use published single-cell RNA-seq data and develop a computational framework to better understand the heterogeneity of tumour metabolism, highlighting the discordance between results obtained from single cells and bulk tumours.

Article | Open Access | | Nature Communications

More featured articles

MAPK-targeted therapies fail to achieve complete remission. Here, the authors show that anti-apoptosis resistance is acquired in these targeted therapies through the mRNA destabilization of NOXA which leads to dependence on MCL-1, and that sequential combination of MCL-1 inhibition with targeted therapies overcomes this resistance.

Article | Open Access | | Nature Communications

The aggressive nature of melanoma cells relies on their ability to switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state; however, the mechanisms governing this switch are unclear. Here, using in vivo models of human melanoma, the authors show that CD271 is a key regulator of phenotype switching and metastasis formation.

Article | Open Access | | Nature Communications

In metastatic melanoma, ADAR1 is downregulated, facilitating proliferation. Here, the authors show an ADAR1-dependent and RNA-editing-independent regulation of melanoma invasion mediated by ITGB3 expression, which can be reversed when ITGB3 is blocked.

Article | Open Access | | Nature Communications

The relationship between autophagy and BRAF signalling is unclear. Here, the authors describe that BRAF inhibition induces the autophagy-lysosomal function in BRAF-mutant melanomas via modulation of the TFEB and ZKSCAN3 transcriptome, which downregulates TGF-β and suppresses melanoma progression.

Article | Open Access | | Nature Communications

In melanoma, reduced ADAR1 impairs A-to-I microRNA editing. Here, the authors show that miR-378a-3p undergoes this editing in non-metastatic cells and the edited form of miR-378a-3p binds to the PARVA oncogene, inhibiting its expression and preventing melanoma progression and metastasis.

Article | Open Access | | Nature Communications

The interaction of DOT1L with MLL oncogenic fusion proteins has been implicated in leukemogenesis. Here, the authors show a contrasting role for DOT1L in protecting UVR-induced melanomagenesis by facilitating DNA repair through interaction with XPC.

Article | Open Access | | Nature Communications

Melanoma persister cells are tolerant to anti-BRAF and anti-MEK inhibition and can trigger cancer relapse. Here the authors show that a subset of N6-methyladenosine modified mRNAs is translationally activated in persister cells. This preferential translation can be abrogated via eIF4A inhibition.

Article | Open Access | | Nature Communications

Exosomes are extracellular vesicles that can favor tumor development and metastasis. Here, the authors show that cancer exosomes may also exert a suppressive function; in fact, exosomes from non-metastatic melanoma cells can lead to the recruitment of patrolling monocytes, which clear cancer cells at the pre-metastatic niche.

Article | Open Access | | Nature Communications

The melanoma-driver mutations in NRAS and BRAF are mutually exclusive but the contribution of RAF signalling downstream of NRAS remains to be clarified. Here, using mouse models, the authors show specific roles of each member of the RAF family at different stages of melanomagenesis.

Article | Open Access | | Nature Communications

Usp9x is a deubiquitinating enzyme with altered expression in melanoma; however its functional contribution in this context is not clear. Here the authors show that Usp9x regulates the stability of the transcription factor Ets-1 that in turn impacts metastatic melanoma through increased expression of NRAS.

Article | Open Access | | Nature Communications

Melanocytic nevus count is associated with melanoma risk. In this study, a meta-analysis of 11 nevus GWAS studies identifies novel SNPs in KITLG and 9q32, and bivariate analysis with melanoma GWAS meta-analysis reveals that most nevus genes affect melanoma risk, while melanoma risk loci do not alter the nevus count.

Article | Open Access | | Nature Communications

Immunotherapy can induce antigen spreading of antitumor T cell response, which correlates with better outcomes. Here the authors show that tissue-resident memory CD8 T cells promote antigen spreading via lysing tumor cells and promoting their uptake and cross-presentation by dendritic cells, thereby eliciting de novo T cell responses.

Article | Open Access | | Nature Communications

The epigenetic mechanisms of melanoma drug resistance are poorly understood. Here, the authors develop a CRISPR-Cas9 screen targeting epigenetic regulators and discover that SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling.

Article | Open Access | | Nature Communications

CCL5 is an important chemokine for modulation of inflammatory responses, but how CCL5 expression is regulated is still unclear. Here the authors show that the CCL5 locus contains two enhancers, with the proximal enhancer being responsible for homeostatic expression and the distal enhancer enforcing inducibility, while both enhancers are modulated by RUNX3.

Article | Open Access | | Nature Communications

Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8+ T cell responses that result in potent tumor suppression.

Article | Open Access | | Nature Communications

Each cell type in the tumour microenvironment has unique metabolic demands enabling specific functions. Here the authors use published single-cell RNA-seq data and develop a computational framework to better understand the heterogeneity of tumour metabolism, highlighting the discordance between results obtained from single cells and bulk tumours.

Article | Open Access | | Nature Communications