RESUMO
Background: Immunotherapy has revolutionized skin cutaneous melanoma treatment, but response variability due to tumor heterogeneity necessitates robust biomarkers for predicting immunotherapy response. Methods: We used weighted gene co-expression network analysis (WGCNA), consensus clustering, and 10 machine learning algorithms to develop the immunotherapy-related gene model (ITRGM) signature. Multi-omics analyses included bulk and single-cell RNA sequencing of melanoma patients, mouse bulk RNA sequencing, and pathology sections of melanoma patients. Results: We identified 66 consensus immunotherapy prognostic genes (CITPGs) using WGCNA and differentially expressed genes (DEGs) from two melanoma cohorts. The CITPG-high group showed better prognosis and enriched immune activities. DEGs between CITPG-high and CITPG-low groups in the TCGA-SKCM cohort were analyzed in three additional melanoma cohorts using univariate Cox regression, resulting in 44 consensus genes. Using 101 machine learning algorithm combinations, we constructed the ITRGM signature based on seven model genes. The ITRGM outperformed 37 published signatures in predicting immunotherapy prognosis across the training cohort, three testing cohorts, and a meta-cohort. It effectively stratified patients into high-risk or low-risk groups for immunotherapy response. The low-risk group, with high levels of model genes, correlated with increased immune characteristics such as tumor mutation burden and immune cell infiltration, indicating immune-hot tumors with a better prognosis. The ITRGM's relationship with the tumor immune microenvironment was further validated in our experiments using pathology sections with GBP5, an important model gene, and CD8 IHC analysis. The ITRGM also predicted better immunotherapy response in eight cohorts, including urothelial carcinoma and stomach adenocarcinoma, indicating broad applicability. Conclusions: The ITRGM signature is a stable and robust predictor for stratifying melanoma patients into 'immune-hot' and 'immune-cold' tumors, enhancing prognosis and response to immunotherapy.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Aprendizado de Máquina , Melanoma , Humanos , Melanoma/terapia , Melanoma/imunologia , Melanoma/genética , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/genética , Animais , Perfilação da Expressão Gênica , Transcriptoma , Regulação Neoplásica da Expressão Gênica , Camundongos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Resultado do Tratamento , Redes Reguladoras de GenesRESUMO
Melanoma is a highly malignant form of skin cancer that typically originates from abnormal melanocytes. Despite significant advances in treating metastatic melanoma with immune checkpoint blockade (ICB) therapy, a substantial number of patients do not respond to this treatment and face risks of recurrence and metastasis. This study collected data from multiple datasets, including cohorts from Riaz et al., Gide et al., MGH, and Abril-Rodriguez et al., focusing on on-treatment samples during ICB therapy. We used the single-sample gene set enrichment analysis (ssGSEA) method to calculate immunogenic cell death scores (ICDS) and employed an elastic network algorithm to construct a model predicting ICB efficacy. By analyzing 18 ICD gene signatures, we identified 9 key ICD gene signatures that effectively predict ICB treatment response for on-treatment metastatic melanoma specimens. Results showed that patients with high ICD scores had significantly higher response rates to ICB therapy compared to those with low ICD scores. ROC analysis demonstrated that the AUC values for both the training and validation sets were around 0.8, indicating good predictive performance. Additionally, survival analysis revealed that patients with high ICD scores had longer progression-free survival (PFS). This study used an elastic network algorithm to identify 9 ICD gene signatures related to the immune response in metastatic melanoma. These gene features can not only predict the efficacy of ICB therapy but also provide references for clinical decision-making. The results indicate that ICD plays an important role in metastatic melanoma immunotherapy and that expressing ICD signatures can more accurately predict ICB treatment response and prognosis for on-treatment metastatic melanoma specimens, thus providing a basis for personalized treatment.
Assuntos
Inibidores de Checkpoint Imunológico , Morte Celular Imunogênica , Melanoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Melanoma/imunologia , Melanoma/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Morte Celular Imunogênica/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/genética , Metástase Neoplásica , Perfilação da Expressão Gênica , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Transcriptoma , PrognósticoRESUMO
Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy characterized by its uncertain etiology and metastatic potential. Surgery remains the first-line clinical treatment for EMPD, but the efficacy of radiotherapy and chemotherapy remains to be fully evaluated, and new therapies for EMPD are urgently needed. In this study, we initially screened 815 EMPD patients in the Surveillance, Epidemiology, and End Results (SEER) database and analyzed their clinical features and prognostic factors. Using the dataset from the Genome Sequence Archive (GSA) database, we subsequently conducted weighted gene coexpression network analysis (WGCNA), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analyses, grouping the samples based on EMPD disease status and the levels of ERBB2 expression. The prognostic analysis based on the SEER database identified increased age at diagnosis, distant metastasis, and receipt of radiotherapy as independent risk factors for EMPD. Moreover, our results indicated that patients who received chemotherapy had worse prognoses than those who did not, highlighting the urgent need for novel treatment approaches for EMPD. Functional analysis of the GSA-derived dataset revealed that EMPD tissues were significantly enriched in immune-related pathways compared with normal skin tissues. Compared with those with high ERBB2 expression, tissues with low ERBB2 expression displayed greater immunogenicity and enrichment of immune pathways, particularly those related to B cells. These findings suggest that patients with low ERBB2 expression are likely to benefit from immunotherapy, especially B-cell-related immunotherapy.
Assuntos
Imunoterapia , Doença de Paget Extramamária , Receptor ErbB-2 , Humanos , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Doença de Paget Extramamária/genética , Doença de Paget Extramamária/terapia , Doença de Paget Extramamária/patologia , Doença de Paget Extramamária/metabolismo , Feminino , Masculino , Idoso , Imunoterapia/métodos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Biomarcadores Tumorais/genética , Idoso de 80 Anos ou mais , Programa de SEER , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Cancer onset and progression are driven by genetic and epigenetic alterations leading to oncogene activation and the silencing of tumor suppressor genes. Among epigenetic mechanisms, DNA methylation (methDNA) is gaining growing interest in cancer. Promoter hypomethylation is associated with oncogene activation while intragenic methDNA can be involved in transcriptional elongation, alternative spicing, and the activation of cryptic start sites. Several genes involved in the modulation of the tumor microenvironment are regulated by methDNA, including the Solute Carrier Family 22 Member 17 (SLC22A17), which is involved in iron trafficking and extracellular matrix remodeling cooperating with the Gelatinase-Associated Lipocalin (NGAL) ligand. However, the exact role of intragenic methDNA in cancer has not been fully investigated. Therefore, the aim of the present study is to explore the role of methDNA in the regulation of SLC22A17 in cutaneous melanoma (CM), used as a tumor model. METHODS: Correlation and differential analyses between SLC22A17 expression and methDNA were performed using the data contained in The Cancer Genome Atlas and Gene Expression Omnibus databases. Functional studies on melanoma cell lines treated with 5-Azacytidine (5-Aza) were conducted to assess the correlation between methDNA and SLC22A17 expression. A validation study on the diagnostic potential of the in silico-identified SLC22A17 methDNA hotspot was finally performed by analyzing tissue samples obtained from CM patients and healthy controls. RESULTS: The computational analyses revealed that SLC22A17 was significantly downregulated in CM, and its expression was related to promoter hypomethylation and intragenic hypermethylation. Moreover, SLC22A17 overexpression and hypermethylation of two intragenic methDNA hotspots were associated with a better clinical outcome in CM patients. The correlation between SLC22A17 methDNA and expression was confirmed in 5-Aza-treated cells. In agreement with in silico analyses, the SLC22A17 promoter methylation hotspot showed higher methDNA levels in CM samples compared to nevi. In addition, the methDNA levels of this hotspot were positively correlated with advanced CM. CONCLUSIONS: The SLC22A17 methDNA hotspot could represent a promising biomarker for CM, highlighting the regulatory role of methDNA on SLC22A17 expression. These results pave the way for the identification of novel epigenetic biomarkers and therapeutic targets for the management of CM patients.
Assuntos
Biomarcadores Tumorais , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Melanoma , Neoplasias Cutâneas , Metilação de DNA/genética , Humanos , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Linhagem Celular Tumoral , Regiões Promotoras Genéticas/genética , Melanoma Maligno Cutâneo , Masculino , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Feminino , Azacitidina/farmacologia , Pessoa de Meia-IdadeRESUMO
Merkel cell polyomavirus (MCPyV) is a significant contributor to the development of Merkel cell carcinoma (MCC), an aggressive skin cancer with high recurrence and a low survival rate. In fact, it is the deadliest skin cancer. The precise routes of transmission for MCPyV-positive MCC remain unclear, but several factors may trigger its development. Conventional treatments for MCC are not highly effective, especially in patients with metastasis, with a clear need for new treatment options. Gene-targeted therapies hold great promise for the treatment of MCC, including the use of siRNA and CRISPR/Cas (C/Cas) but critically none have yet been translated into clinical trials. Validating this approach is the fact that several siRNA products are already FDA licenced, while C/Cas has entered clinical trial, albeit for conditions other than MCC. There are many challenges that must be overcome to move from preclinical research to the clinic. In this review, we provide a comprehensive summary of the current understanding of MCC, with a particular focus on MCPyV-positive MCC, and the status of gene-targeted therapies. Additionally, we discuss the major obstacles that impede MCC research and explore future prospects.
Assuntos
Carcinoma de Célula de Merkel , Terapia Genética , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Humanos , Poliomavírus das Células de Merkel/genética , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/terapia , Carcinoma de Célula de Merkel/genética , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/terapia , Terapia Genética/métodos , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/genética , Animais , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/terapia , RNA Interferente Pequeno/genéticaRESUMO
The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.
Assuntos
Anti-Hipertensivos , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Anti-Hipertensivos/farmacologia , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Bisoprolol/farmacologia , Bisoprolol/uso terapêutico , Nitrosaminas , Masculino , Hidroclorotiazida/farmacologia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Carcinoma Basocelular/genética , Antiarrítmicos/farmacologia , Feminino , Reprogramação MetabólicaRESUMO
BACKGROUND: Most primary cutaneous melanomas have pathogenesis driven by ultraviolet exposure and genetic mutations, whereas acral lentiginous melanoma (ALM) and metastatic melanoma are much less, if at all, linked with the former. Thus, we evaluated both ultraviolet related and non-ultraviolet related melanomas. Mutations in the MUC16 and TTN genes commonly occur concurrently in these melanoma patients, but their combined prognostic significance stratified by gender and cancer subtype remains unclear. METHODS: The cBioPortal database was queried for melanoma studies and returned 16 independent studies. Data from 2447 melanoma patients were utilized including those with ALM, cutaneous melanoma (CM), and melanoma of unknown primary (MUP). Patients were grouped based on the presence or absence of MUC16 and TTN mutations. Univariate Cox regression and Student's t-tests were used to analyze hazard ratios and total mutation count comparisons, respectively. RESULTS: TTN mutations, either alone or concurrently with MUC16 mutations, significantly correlated with worse prognosis overall, in both genders, and in CM patients. ALM patients with both mutations had better prognoses than CM patients, while ALM patients with neither mutation had worse prognosis than CM patients. For MUP patients, only MUC16 mutations correlated with worse prognosis. ALM patients with neither MUC16 nor TTN mutations had significantly more total mutations than MUP patients, followed by CM patients. CONCLUSION: TTN mutations are a potential marker of poor prognosis in melanoma, which is amplified in the presence of concurrent MUC16 mutations. ALM patients with neither gene mutations had worse prognosis, suggesting a protective effect of having both MUC16 and TTN mutations. Only MUC16 mutations conferred a worse prognosis for MUP patients. Comprehensive genetic profiling in melanoma patients may facilitate personalized treatment strategies to optimize patient outcomes.
Assuntos
Conectina , Melanoma , Mutação , Neoplasias Cutâneas , Humanos , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Feminino , Masculino , Prognóstico , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Conectina/genética , Antígeno Ca-125 , Fatores Sexuais , Proteínas de Membrana/genética , Idoso , Biomarcadores Tumorais/genética , AdultoRESUMO
AIM: We aimed to explore the impact of DNA methylation alterations on the DNA damage response (DDR) in melanoma prognosis and immunity. MATERIAL & METHODS: Different melanoma cohorts with molecular and clinical data were included. RESULTS: Hierarchical clustering utilizing different combinations of DDR-relevant CpGs yielded distinct melanoma subtypes, which were characteristic of different prognoses, transcriptional function profiles of DDR, and immunity and immunotherapy responses but were associated with similar tumor mutation burdens. We then constructed and validated a clinically applicable 4-CpG risk-score signature for predicting survival and immunotherapy response. CONCLUSION: Our study describes the close interrelationship among DNA methylation, DDR machinery, local tumor immune status, melanoma prognosis, and immunotherapy response.
Assuntos
Dano ao DNA , Metilação de DNA , Melanoma , Melanoma/genética , Melanoma/imunologia , Melanoma/mortalidade , Humanos , Prognóstico , Imunoterapia/métodos , Ilhas de CpG , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Regulação Neoplásica da Expressão Gênica/imunologia , MutaçãoRESUMO
Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient's response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan-Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003-0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011-0.260; p < 0.0001). The Kaplan-Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071-0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05-0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2-3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5-9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma.
Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Proteômica , Transcriptoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Melanoma/mortalidade , Feminino , Masculino , Estudos Retrospectivos , Proteômica/métodos , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Biomarcadores Tumorais/genética , Adulto , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteoma/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/metabolismo , Metástase NeoplásicaRESUMO
We previously showed that inhibition of glycolysis in cutaneous squamous cell carcinoma (SCC)-initiating cells had no effect on tumorigenesis, despite the perceived requirement of the Warburg effect, which was thought to drive carcinogenesis. Instead, these SCCs were metabolically flexible and sustained growth through glutaminolysis, another metabolic process frequently implicated to fuel tumorigenesis in various cancers. Here, we focused on glutaminolysis and genetically blocked this process through glutaminase (GLS) deletion in SCC cells of origin. Genetic deletion of GLS had little effect on tumorigenesis due to the up-regulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We went on to show that posttranscriptional regulation of nutrient transporters appears to mediate metabolic flexibility in this SCC model. To define the limits of this flexibility, we genetically blocked both glycolysis and glutaminolysis simultaneously and found the abrogation of both of these carbon utilization pathways was enough to prevent both papilloma and frank carcinoma.
Assuntos
Carcinoma de Células Escamosas , Glutaminase , Glicólise , Folículo Piloso , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/genética , Animais , Folículo Piloso/metabolismo , Glutaminase/metabolismo , Glutaminase/genética , Camundongos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Células-Tronco/metabolismo , Glutamina/metabolismo , Humanos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/genética , Carcinogênese/metabolismo , Carcinogênese/genéticaRESUMO
The establishment of immunotherapy applying immune checkpoint inhibitors (ICI) has provided an important new option for the treatment of solid malignant diseases. However, different tumor entities show dramatically different responses to this therapy. BCC responds worse to anti-PD-1 ICIs as compared to cSCC. Differential immune checkpoint expression could explain this discrepancy and, therefore, the aim of this study was to analyze activating and inhibitory immune checkpoints in cSCC and BCC tissues. Tissue microarrays of the invasive front as well as the tumor core of BCC and cSCC samples were used to evaluate PD-1, PD-L1, CD28, and CD86 expression and their topographic distribution profiles by chromogenic immunohistochemistry. QuPath was used to determine the labeling index. The expression of PD-1, PD-L1, and CD28 was significantly higher in both the tumor core and the invasive front of cSCC samples as compared to BCC (p < 0.001). In addition, the ratios of PD-L1/CD86 (p < 0.001) and CD28/CD86 (p < 0.001) were significantly higher in cSCC. The invasive front of both tumor entities showed higher expression levels of all immune markers compared to the tumor core in both tumor entities. The significantly higher expression of PD-1, PD-L1, and CD28 in cSCC, along with the predominance of the inhibitory ligand PD-L1 as compared to the activating CD86 in cSCC, provide a potential explanation for the better objective response rates to anti-PD-1 immunotherapy as compared to BCC. Furthermore, the predominant site of interaction between the immune system and the tumor was within the invasive front in both tumor types.
Assuntos
Antígeno B7-2 , Antígeno B7-H1 , Antígenos CD28 , Receptor de Morte Celular Programada 1 , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/genética , Antígenos CD28/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-2/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso , Carcinoma Basocelular/imunologia , Carcinoma Basocelular/patologia , Carcinoma Basocelular/metabolismoRESUMO
Squamous cell carcinoma (SCC) is a common skin cancer, often caused by exposure to ultraviolet radiation (UVR). Recent studies have shown that changes in DNA methylation play a crucial role in the development of cancers. However, methylation patterns of SCC are not well characterised. Identifying biomarkers for the risk of developing SCC could be helpful for early detection and diagnosis and can potentially improve treatment and prevention strategies. This study aimed to investigate methylation changes in the epidermis of mice exposed to UVR for 24 weeks. We examined the DNA methylation levels of 260 199 CpGs using the Illumina Infinium Mouse Methylation BeadChip and studied the epidermis of UVR-exposed and unexposed mice every 4 weeks for 24 weeks (n = 39). We identified CpGs with large differences in methylation levels (ß-values) between UVR-exposed and unexposed mice. We also observed differences in the epigenetic age of these mice. We identified CpGs in Rev, Ipmk, Rad51b, Fgfr2, Fgfr3 and Ctnnb1 that may serve as potential biomarkers for SCC risk and could be helpful for the early detection and prevention of SCC. Further investigations are necessary to determine the biological functions and clinical significance of these CpGs.
Assuntos
Carcinoma de Células Escamosas , Metilação de DNA , Epiderme , Neoplasias Cutâneas , Raios Ultravioleta , Animais , Carcinoma de Células Escamosas/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/etiologia , Raios Ultravioleta/efeitos adversos , Camundongos , Epiderme/efeitos da radiação , Epiderme/metabolismo , Epigênese Genética , Ilhas de CpG , Feminino , Biomarcadores Tumorais/genética , beta Catenina/metabolismo , beta Catenina/genética , Neoplasias Induzidas por Radiação/genéticaRESUMO
Malignant skin tumors mainly include basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. There is currently observational research suggesting that changes in cathepsin (CTS) may be a factor in the development of malignant skin tumors, but no studies have yet demonstrated a causal relationship between tissue protease changes and the occurrence of malignant skin tumors. Current studies have shown that cathepsin is involved in tumor cell invasion and metastasis by regulating growth factors and cellular immune function in tumor microenvironment, decomposing extracellular matrix and basement membrane, and promoting angiogenesis. In this study, we conducted a bidirectional Mendelian-randomization study using publicly available genome-wide association study (GWAS; GWAS Catalog) data. This study applies a bidirectional multivariate Mendelian randomization (MR) approach to investigate the causal relationship between cathepsin, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. In cases where multiple cathepsins are implicated as etiological factors in certain diseases, a multivariable analysis is conducted to assess the direct and indirect causal effects of the exposure factors. In this study, we present a comprehensive MR analysis to investigate the relationship between 9 cathepsin and basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Based on our MR analysis using the largest GWAS Catalog dataset available, we are able to draw relatively reliable conclusions. In the MR study, we found that tissue protease L2 can promote skin cancer, Cathepsin O, and Cathepsin F are associated with an increased risk of basal cell carcinoma. Cathepsin H can inhibit basal cell carcinoma and malignant melanoma. In the reverse MR study, it was found that squamous cell carcinoma may cause an increase in Cathepsin O expression. In the multivariate analysis, it was found that Cathepsin H is a direct factor in reducing the occurrence of skin cancer and melanoma, with no apparent causal relationship to non-melanoma skin cancer. Cathepsin has a dual impact on skin cancer cells, and the expression of different cathepsins at the edge of skin tumors may indicate different developmental tendencies of skin cancer. Cathepsin may serve as effective biomarkers for predicting tumors.
Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Catepsinas , Estudo de Associação Genômica Ampla , Melanoma , Análise da Randomização Mendeliana , Neoplasias Cutâneas , Neoplasias Cutâneas/genética , Humanos , Catepsinas/genética , Catepsinas/metabolismo , Carcinoma Basocelular/genética , Carcinoma Basocelular/epidemiologia , Carcinoma de Células Escamosas/genética , Melanoma/genética , Análise MultivariadaRESUMO
The large T antigen (LT) of the Merkel cell polyomavirus (MCPyV) is crucial for Merkel cell carcinoma (MCC), a rare but very aggressive form of neuroendocrine skin cancer. The clonal integration of MCPyV DNA into the host genome is a signature event of this malignancy. The resulting expression of oncogenes, including the small T (sT) antigen and a truncated form of the LT (truncLT), directly contribute to carcinogenesis. The truncation of the C-terminus of LT prevents the virus from replicating due to the loss of the origin binding domain (OBD) and the helicase domain. This precludes cytopathic effects that would lead to DNA damage and ultimately cell death. At the same time, the LxCxE motif in the N-terminus is retained, allowing truncLT to bind the retinoblastoma protein (pRb), a cellular tumor suppressor. The continuously inactivated pRb promotes cell proliferation and tumor development. truncLT exerts several classical functions of an oncogene: altering the host cell cycle, suppressing innate immune responses to viral DNA, causing immune escape, and shifting metabolism in favor of cancer cells. Given its central role in MCC, the LT is a major target for therapeutic interventions with novel approaches, such as immune checkpoint inhibition, T cell-based immunotherapy, and cancer vaccines.
Assuntos
Antígenos Virais de Tumores , Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/imunologia , Humanos , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/patogenicidade , Poliomavírus das Células de Merkel/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/imunologia , Infecções Tumorais por Vírus/virologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/genética , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/genéticaRESUMO
Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.
Assuntos
Vesículas Extracelulares , Fibroblastos , Melanoma , Neovascularização Patológica , Tetraspanina 29 , Vesículas Extracelulares/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Humanos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Tetraspanina 29/metabolismo , Tetraspanina 29/genética , Microambiente Tumoral , Linhagem Celular Tumoral , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Animais , AngiogêneseRESUMO
Ferroptosis, a key factor in tumor progression, is poorly understood at the molecular level. This study investigates how ELK4 and CHMP6 regulate skin cutaneous melanoma (SKCM) cell proliferation and ferroptosis. Analysis of TCGA data reveals high expression of ELK4 and CHMP6 in SKCM. Overexpression of ELK4 or CHMP6 enhances cell proliferation, invasion, and migration while reducing ROS and Fe2 + levels. It also increases GPX4 and xCT expression and decreases ACSL4 levels in SKCM cells. The opposite effects are observed with ELK4 or CHMP6 knockdown. ELK4 binds to the CHMP6 promoter, promoting CHMP6 transcription. Knockdown of CHMP6 reverses the oncogenic effects of ELK4 overexpression. In conclusion, ELK4 enhances proliferation, invasion, and migration while inhibiting ferroptosis in SKCM cells by upregulating CHMP6 transcription. This study sheds light on the intricate mechanisms involved in SKCM progression and identifies potential therapeutic targets in melanoma treatment.
Assuntos
Movimento Celular , Proliferação de Células , Ferroptose , Regulação Neoplásica da Expressão Gênica , Melanoma , Neoplasias Cutâneas , Humanos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Ferroptose/genética , Melanoma/patologia , Melanoma/genética , Melanoma/metabolismo , Melanoma Maligno Cutâneo , Invasividade Neoplásica/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
Immunotherapeutic drugs are promising medicines for cancer treatment. A potential candidate for immunotherapy is interleukin-12 (IL-12), a cytokine well known for its ability to mediate antitumor activity. We developed a plasmid encoding human IL-12 devoid of an antibiotic resistance gene (phIL12). For the approval of phase I clinical trials in basal cell carcinoma (BCC), the regulatory agency requires non-clinical in vivo testing of the pharmacodynamic, pharmacokinetic and toxicological properties of the plasmid. As human IL-12 is not biologically active in mice, a mouse ortholog of the plasmid phIL12 (pmIL12) was evaluated. The evaluation demonstrated the antitumor effectiveness of the protein accompanied by immune cell infiltration. The plasmid was distributed throughout the body, and the amount of plasmid diminished over time in all organs except the skin around the tumor. The therapy did not cause any detectable systemic toxicity. The results of the non-clinical evaluation demonstrated the safety and efficacy of the pmIL12/phIL12 GET, and on the basis of these results, approval was obtained for the initiation of a phase I clinical study in BCC.
Assuntos
Terapia Genética , Interleucina-12 , Animais , Interleucina-12/genética , Camundongos , Humanos , Terapia Genética/métodos , Plasmídeos/genética , Carcinoma Basocelular/terapia , Carcinoma Basocelular/genética , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/imunologia , Ensaios Clínicos Fase I como Assunto , Feminino , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologiaRESUMO
In the era of next-generation sequencing, the genetic background of cancer, including melanoma, appears to be thoroughly established. However, evaluating the oncogene BRAF mutation in codon V600 is still the only companion diagnostic genomic test commonly implemented in clinics for molecularly targeted treatment of advanced melanoma. Are we wasting the collected genomic data? Will we implement our current genomic knowledge of melanoma in clinics soon? This question is rather urgent because new therapeutic targets and biomarkers are needed to implement more personalized, patient-tailored therapy in clinics. Here, we provide an update on the molecular background of melanoma, including a description of four already established molecular subtypes: BRAF+, NRAS+, NF1+, and triple WT, as well as relatively new NGS-derived melanoma genes such as PREX2, ERBB4, PPP6C, FBXW7, PIK3CA, and IDH1. We also present a comparison of genomic profiles obtained in recent years with a focus on the most common melanoma genes. Finally, we propose our melanoma gene panel consisting of 22 genes that, in our opinion, are "must-have" genes in both melanoma-specific genomic tests and pan-cancer tests established to improve the treatment of melanoma further.
Assuntos
Genômica , Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Genômica/métodos , Mutação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Biomarcadores Tumorais/genética , Neoplasias Cutâneas/genéticaRESUMO
Disulfidptosis, the newest form of programmed cell death, is closely associated with the immune microenvironment of cancer cells. Long non-coding RNA (lncRNA) has also been found to play a crucial role in melanoma. However, the role of disulfidptosis-related lncRNA in melanoma remains unclear. Through bioinformatic analysis of the transcriptional, clinical, and pathological data from the TCGA-SKCM (The Cancer Genome Atlas-Skin cutaneous melanoma) database, we established a 2-Disulfidptosis-related lncRNA (DRL) prognostic model and a novel molecular subtype for melanoma. The survival and ROC curves of the 2-DRL prognostic model demonstrated its strong efficacy in predicting the prognosis of melanoma. The high-risk group of melanoma exhibited a significant decrease in ESTIMATEScore, ImmuneScore, and StromalScore, indicative of pronounced immune suppression and exhaustion. Subgroup C2 of melanoma displayed an immune-activated state, while subgroups C1 and C3 showed immune suppression and exhaustion, potentially leading to poorer prognosis. Subgroup C1 demonstrated better sensitivity to Zoledronate, UMI-77, Nilotinib, and Cytarabine. Subgroup C2 exhibited greater sensitivity to Ribociclib, XAV939, Topotecan, and Ruxolitinib. Subgroup C3 showed higher sensitivity to VX-11e, Ulixertinib, Trametinib, and Afatinib. This study revealed the immune microenvironment status and targeted drug sensitivity in melanoma patients with different risk scores and molecular subtypes, offering valuable guidance for clinical treatment and identifying significant DRL targets for future in-depth research.
Assuntos
Melanoma , RNA Longo não Codificante , Humanos , Melanoma/genética , Melanoma/tratamento farmacológico , Melanoma/patologia , RNA Longo não Codificante/genética , Prognóstico , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Biomarcadores Tumorais/genéticaRESUMO
Melanoma is the most severe type of skin cancer and among the most malignant neoplasms in humans. With the growing incidence of melanoma, increased numbers of therapeutic options, and the potential to target specific proteins, understanding the basic mechanisms underlying the disease's progression and resistance to treatment has never been more important. LOXL3, SNAI1, and NES are key factors in melanoma genesis, regulating tumor growth, metastasis, and cellular differentiation. In our study, we explored the potential role of LOXL3, SNAI1, and NES in melanoma progression and metastasis among patients with dysplastic nevi, melanoma in situ, and BRAF+ and BRAF- metastatic melanoma, using immunofluorescence and qPCR analysis. Our results reveal a significant increase in LOXL3 expression and the highest NES expression in BRAF+ melanoma compared to BRAF-, dysplastic nevi, and melanoma in situ. As for SNAI1, the highest expression was observed in the metastatic melanoma group, without significant differences among groups. We found co-expression of LOXL3 and SNAI1 in the perinuclear area of all investigated subgroups and NES and SNAI1 co-expression in melanoma cells. These findings suggest a codependence or collaboration between these markers in melanoma EMT, suggesting new potential therapeutic interventions to block the EMT cascade that could significantly affect survival in many melanoma patients.