Search Results (1,109)

Melanoma is a highly aggressive malignancy characterized by pronounced metastatic potential, marked heterogeneity, and complex therapeutic resistance. Although immunotherapy and targeted therapy have improved the prognosis of some patients, their long-term clinical application remains constrained by limited therapeutic responses, drug resistance, and adverse effects. In this study, widely targeted metabolomics, network pharmacology, molecular docking, and molecular dynamics simulations were integrated to systematically investigate the potential mechanisms underlying the anti-melanoma effects of Inonotus hispidus SH-18. Fruiting bodies of Sang Huang at the Juvenile, Growth, and Maturation stages were analyzed using UPLC-MS/MS, identifying 1575 metabolites across 13 chemical classes. PCA explained 67.91% of the total variance (PC1, 43.54%; PC2, 24.37%), while the OPLS-DA models yielded Q² values of 0.964, 0.966, and 0.981 for IH-G vs. IH-J, IH-M vs. IH-G, and IH-M vs. IH-J, respectively. A total of 1099 differentially accumulated metabolites were identified, including 304 (140 up-accumulated and 164 down-accumulated), 311 (195 up-accumulated and 116 down-accumulated), and 484 (278 up-accumulated and 206 down-accumulated) in the three respective comparisons. Based on the experimentally detected metabolites, network pharmacology and bioinformatics analyses suggested that the active constituents of Sang Huang may synergistically suppress melanoma cell proliferation, survival, immune evasion, angiogenesis, invasion, and metastasis by regulating multiple pathways and signaling axes, including the TP53-p21 axis. Molecular docking showed that the candidate active compounds exhibited binding potential with core targets, among which ursolic acid displayed favorable binding capacity toward all core targets. Molecular dynamics simulations further supported the stability of these interactions. Notably, ursolic acid was most abundant in samples from the Juvenile stage, suggesting that this stage may be preferred for ursolic acid enrichment and subsequent activity evaluation. These findings suggest the potential therapeutic value of Sang Huang in melanoma treatment. Full article

Growth factors are molecules that interact with specific membrane receptors and induce cellular proliferation. In malignancy, this growth factor–receptor interaction constitutes one of the “hallmarks of cancer” and may result in uncontrolled cell growth. Proadrenomedullin N-terminal 20 peptide (PAMP) derives from proadrenomedullin and acts as an angiogenic peptide, and recent studies suggest it may be a tumor growth factor. In addition, it has been suggested that CXCR7 may be PAMP’s membrane receptor in particular cell types. Here, we combined advanced docking and molecular dynamic simulation studies to evaluate PAMP’s binding to CXCR7. Then, we used two melanoma cell lines and checked whether PAMP influences their shape, proliferation, migration, and invasion capacities. The signal transduction activated by PAMP was tested by Western blotting, and receptor involvement was investigated with specific inhibitors. This study shows that PAMP binds to active site 1 of CXCR7. It also increases melanoma cell proliferation through an autocrine growth loop. In contrast, PAMP reduced migration and invasion of these cells in a dose-dependent manner. PAMP was also responsible for modifying the actin cytoskeleton of both cell lines, producing a more elongated morphology. In addition, the presence of PAMP elevated ERK and AKT phosphorylation and increased CXCR7 and β-arrestin expression. Furthermore, specific inhibitors confirmed that these effects are mediated by the CXCR7/CXCR4/β-arrestin axis. In summary, we have shown that PAMP acts as a growth factor for melanoma cells while reducing their migration and invasion potential. These effects seem to be mediated by the CXCR7/CXCR4/β-arrestin axis. Altogether, these results suggest that PAMP inhibitors may be used as antitumor agents in melanoma. Full article

Background: Previous studies have examined bioactive constituents of Prunus dulcis oil, Pinus sylvestris essential oil, and related phytochemical matrices separately; however, their combined chemical profile, comparator-context molecular-docking landscape, and comparative cellular response in melanoma and non-malignant fibroblast models remain insufficiently characterized. Methods: The analyzed study samples were profiled by GC/MS and GC/FID-based fatty-acid methyl ester analysis. An archived molecular-docking dataset was used to summarize structurally plausible interactions of six formulation-associated markers with eight melanoma-relevant or melanoma-adjacent targets and to present representative three-dimensional complexes. Because complete protocol metadata and co-crystallized-ligand redocking records were unavailable, the computational findings were interpreted descriptively. Neutral-red uptake assays assessed the 24 h viability of B16F10 melanoma cells and MRC-5 fibroblasts after exposure to each oil, the dual-oil formulation, or cisplatin. Four-parameter logistic models provided estimated IC₅₀ values, and exact two-sided permutation tests were used for Spearman rank analyses. Results: The dual-oil formulation yielded estimated IC₅₀ values of 1.42% v/v in B16F10 cells and 4.85% v/v in MRC-5 cells, corresponding to an apparent selectivity index of 3.41. The complete eight-concentration series was non-monotonic and showed no significant rank association (B16F10: ρs = −0.4286, exact p = 0.2992; MRC-5: ρs = −0.3810, exact p = 0.3599). In a post hoc analysis of the descending branch (≥0.37% v/v), the association was perfect in B16F10 cells (ρs = −1.0000, exact p = 0.0167) but did not reach significance in MRC-5 cells (ρs = −0.9000, exact p = 0.0833). The docking matrix identified target-dependent numerical prioritization patterns; however, small score differences were not interpreted as evidence of stronger binding or cellular target engagement. Conclusions: The findings define an exploratory chemical–computational–cellular framework and a preliminary formulation-level viability phenotype. They do not establish synergy, apoptosis, pathway modulation, therapeutic efficacy, or clinical safety. Independent multi-batch chemical confirmation, a fully documented and redocking-validated computational protocol, expanded melanoma and normal-skin cell panels, orthogonal functional assays, longer exposure periods, mechanistic validation, and subsequent in vivo studies are required. Full article

Background/Objectives: Metatypical basal cell carcinoma (MTBCC) is a rare and aggressive variant of non-melanoma skin cancer (NMSC) characterised by overlapping histological features of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Owing to its increased propensity for local invasion, recurrence, and metastasis, MTBCC poses diagnostic and therapeutic challenges. This study aimed to characterise the epidemiological, histopathological, and clinical features of MTBCC and to evaluate temporal changes in tumour characteristics and aggressiveness before, during, and after the COVID-19 pandemic. Methods: A retrospective cohort study was conducted on 129 histologically confirmed MTBCC lesions diagnosed in the Pathology Department of the Mures Clinical County Hospital, Targu Mures, Romania, between January 2017 and December 2025. Demographic data, tumour location, histological subtypes, differentiation of the squamous component, aggressiveness parameters, and volumetric measurements of tumours and excision specimens were analysed. Volumetric analyses were restricted to cases with complete three-dimensional measurements. Statistical comparisons were performed across demographic variables and the following three time periods: pre-pandemic, pandemic, and post-pandemic. Results: The median age at diagnosis was 71 years, with a slight male predominance (p = 0.25) and a significant predominance of patients from urban areas (p < 0.001). Most tumours were located in the head and neck region. Mixed-type MTBCC was significantly associated with higher tumour aggressiveness (p = 0.0019) and with high-risk histological subtypes, particularly micronodular and adenoid–cystic variants. Tumour volume showed a significant inverse correlation with year of diagnosis (p = 0.0139; r = (−) 0.50), whereas excision specimen volume differed significantly according to year of diagnosis (p = 0.0425). Neither tumour volume nor excision specimen volume was associated with histopathological aggressiveness. Conclusions: Metatypical basal cell carcinoma is a rare skin malignancy in which biological behaviour appears to be determined primarily by histopathological architecture rather than tumour size. Mixed-type lesions were associated with significantly higher aggressiveness, underscoring the need for accurate histopathological assessment. These findings support a pathology-driven approach to management and emphasise the importance of adequate surgical treatment and long-term follow-up in patients with MTBCC. Full article

Cutaneous melanoma and basal cell carcinoma (BCC) represent the two primary malignancies driven by solar ultraviolet (UV) radiation. To map the spatial topology and distance dependence of their mutational signatures, we deployed new analytical bioinformatics workflow utilizing two convergent strategies: a data-driven read-level phasing framework to discriminate between collateral mutational events versus independent ones and a hypothesis-driven spatial permutational simulation model to capture density-dependent local deviations. A whole-genome analysis employing this framework unexpectedly reveals two fundamentally distinct lesion-processing landscapes, present in both BCC and melanoma. While independent mutations consistently reproduce canonical UV signatures (SBS7a–c) in both tumor types, collateral mutations tell a distinct and more varied narrative between BCC and melanoma. These collateral mutations are unusually abundant for non-UV characteristics, such as age-related SBS1 and SBS5, and display a notable 3′ to 5′ asymmetry near UV-induced lesions in pyrimidine dimers. We also demonstrated that BCC displays a pronounced enrichment of dinucleotide base substitutions flanking UV-signature sites on the 3′ side, particularly CA>TG and CG>TA changes. Ultimately, these topological patterns in both tumors indicate that a primary photoproduct seeds secondary mutagenesis within its local chromatin environment, dramatically altering our understanding of UV-induced lesion processing. Full article

Malignant melanoma demonstrates strikingly varied clinical presentations, on account of which it is often challenging to diagnose. We describe herein a rare case of amelanotic malignant melanoma (AMM) in the buccinator muscle presenting as a solitary mass. A middle-aged woman presented with a non-pigmented swelling under the right buccal mucosa. Magnetic resonance imaging (MRI) revealed a well-circumscribed lesion without local invasion. A needle biopsy did not establish the diagnosis and was instead interpreted as suggestive of a salivary gland tumor, reinforcing an initial impression of myoepithelioma. Histopathological analysis of an excised specimen revealed poorly defined, pleomorphic tumor cells and a scattering of melanin-containing cells. The diagnosis of AMM was established by integrating these histopathological features with the clinico-radiological findings and the immunohistochemical results, which were positive for HMB-45, S-100, and SOX10 and negative for cytokeratin. Whole-body positron-emission tomography-computed tomography found no primary lesion. Because tumor nests suggesting possible residual disease were observed near the resection margin, a wider, secondary excision including the affected portion of the buccal mucosa and overlying skin was performed together with neck dissection. Histopathological examination of the re-resection specimen showed no residual tumor, indicating that no malignant cells were identified in the adjacent oral mucosa or facial skin. The patient has remained disease-free for three years. Full article

Zinc oxide nanobiocomposites were successfully synthesized using a green synthesis approach based on the isoflavone Puerarin, resulting in the formation of PUE-ZnO NPs. Building on their previous physicochemical and in ovo characterization, the present study aimed to comparatively evaluate the biological response induced by PUE-ZnO NPs in non-tumorigenic HaCaT keratinocytes and A375 melanoma cells. Cell viability was assessed by MTT assay, and the cellular response was further investigated through bright-field morphological evaluation, Hoechst 33342 nuclear staining, MitoTracker mitochondrial staining, and clonogenic assay. PUE-ZnO NPs showed a favorable cytocompatibility profile in HaCaT cells, with viability remaining above 80% at the highest tested concentration and only moderate impairment of clonogenic capacity at higher concentrations. In contrast, A375 melanoma cells exhibited a stronger response, characterized by reduced viability, marked morphological alterations, nuclear changes, mitochondrial staining disruption, and a pronounced decrease in colony-forming ability. PUE-ZnO NPs may represent a promising phytochemical-assisted ZnO-based nanosystem for further investigation in melanoma-related models. Full article

Melittin (Mel), the principal cytolytic peptide in honeybee venom (BV), has anticancer activity but limited selectivity. This study examined whether adsorption of Mel to Fe₃O₄ magnetic nanoparticles (MNPs and MNPs-Mel, respectively), alone or combined with magnetic hyperthermia (MH), modifies cytotoxicity and cell-death phenotype in A375 melanoma cells relative to HaCaT keratinocytes. BV, free Mel, and phospholipase A₂ (PLA) were first screened by Alamar Blue assay to select dose-matched conditions; MNPs-Mel (50 or 100 µg/mL MNPs, equivalent to approximately 3 or 6 µg/mL Mel) was then compared with dose-matched free Mel and unfunctionalized MNPs, and the MNP-containing groups were additionally evaluated with MH. Outcomes included metabolic activity, Annexin V/propidium iodide flow cytometry, transmission electron microscopy (TEM), and clonogenic potential. At the lower dose, MNPs-Mel produced a larger Annexin-positive fraction in A375 than in HaCaT cells (28.30% vs. 11.80%) and a lower viable-cell fraction (71.64% vs. 87.55%); relative to dose-matched free Mel, the A375 response shifted toward early apoptosis. After MNPs-Mel plus MH, too few A375 cells remained for reliable cytometric acquisition, whereas HaCaT populations remained quantifiable and showed 25.56–29.45% apoptosis, predominantly late apoptosis. Free PLA produced smaller changes in metabolic activity than BV or Mel at composition-matched concentrations. TEM supported nanoparticle internalization and treatment-associated mitochondrial and lysosomal alterations. These findings suggest that MNP association changes the cellular presentation of low-dose Mel, while MH increases overall treatment intensity but may narrow the separation between malignant and nonmalignant cells. Full article

Melanoma is a malignant tumor that originates in pigment-producing cells called melanocytes. This type of cancer remains a major public health challenge due to its high metastatic potential and resistance to treatment. Autophagy is a catabolic process that enables the controlled degradation of damaged cellular organelles and unnecessary or abnormal macromolecules. Its primary function is to maintain intracellular homeostasis and cell survival. There are three main types of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The role of autophagy in oncogenesis is multifaceted and context-dependent—depending on the type of cancer and its stage of development. Autophagy can either promote tumor progression or act as a tumor-suppressive mechanism. Factors influencing the role of autophagy in cancer include inflammation, crosstalk with apoptosis and resistance to anticancer therapies. Current research is focused on the use of both autophagy inhibitors and autophagy inducers as potential strategies to improve the effectiveness of melanoma treatment. Full article

Background/Objectives: To date there is a lack of an integrative review literature on redox homeostasis, oxidative stress and the influence on metabolic pathways and plasticity in uveal melanoma (UM), since most literature findings are from cutaneous melanoma (CM), a genetically and behaviorally distinct cancer. Furthermore, UM metabolic pathway comparison to other cancers could provide more insight into metastatic UM, a difficult-to-treat malignancy. Methods: A wide-ranging multi-step literature search of PubMed and Web of Science for redox balance, oxidative stress, antioxidants and metabolic plasticity in UM, with expanded search terms for connections with other cancers. Results: UM cells maintain redox homeostasis via several redox loops: glutathione, thioredoxin, peroxiredoxins, peroxisomal catalase and the mitochondrial antioxidative network. NADPH plays a key role in regenerating UM antioxidative capabilities. Key redox signaling pathways are the subject of ongoing research in UM: NRF2 signaling, AMPK, mTOR, MAPK, FoxO. These pathways are less studied versus CM and present behavior differences in UM. PON2, studied in CM, represents a literature gap in UM. Inside the tumoral microenvironment, UM presents high metabolic plasticity and easy switching from glycolysis to oxidative phosphorylation (OXPHOS). Thus, UM eschews the classic Warburg effect loop and instead presents high oxidative phosphorylation (OXPHOS) gene expression, which generates additional lactate, which in turn produces cascade reprogramming in the metabolic pathways and lactate metabolism particularities associated in experimental studies with immune-escape phenomena. Uveal melanoma’s OXPHOS capabilities confer survival advantages and subdivide tumoral populations into OXPHOS-high and OXPHOS-low variants. Glycolysis/OXPHOS metabolic plasticity is an ongoing research field in other cancers with common and different elements vs. UM: cutaneous melanoma, small cell lung carcinoma, pancreatic cancer, breast cancer, acute myeloid leukemia, prostate cancer, renal cell carcinoma and glioblastoma. Uveal melanoma cells are susceptible to deleterious effects of prooxidants, a metabolic vulnerability which helps to create genetic pleomorphism, selecting higher proliferation and dissemination variants. Conclusions: Uveal melanoma is an oncogenic mutation and mitochondrial metabolism-driven malignancy, with metabolic connections to other malignancies. Emerging understanding of redox homeostasis, redox pathway signaling, mitochondrial oxidative and oncogenic metabolism could lead to better understanding of therapeutic response and new therapeutic targets. This review novelly integrates the general and CM redox literature with the UM literature, painting a complex redox signaling and metabolic plasticity picture of UM. Full article

Multiple myeloma (MM) remains an incurable hematological malignancy in which tumor-intrinsic immune evasion limits the efficacy of immunotherapy. Here, we identify the RNA editing enzyme ADAR1 as a key regulator of innate immune suppression in MM. Integrative analyses of bulk and single-cell transcriptomic datasets, together with clinical validation, demonstrated that ADAR1 is upregulated in malignant plasma cells and is associated with adverse clinical outcomes and reduced CD8⁺ T-cell infiltration. Mechanistically, ADAR1 knockdown increased the association of endogenous dsRNA with melanoma differentiation-associated protein 5 (MDA5), restoring type I interferon (IFN) signaling, enhancing IFNα production and STAT1 activation, and promoting CD8⁺ T-cell proliferation and cytotoxic function. These effects were largely abolished by MDA5 depletion, establishing a functional ADAR1–MDA5 signaling axis in MM. In vivo, treatment with 8-azaadenosine significantly potentiated the antitumor efficacy of PD-1 blockade, resulting in reduced tumor growth, increased tumor cell apoptosis, elevated IFNα expression, and enhanced CD8⁺ T-cell infiltration. Together, our findings demonstrate that ADAR1-mediated RNA editing enables immune evasion by restricting MDA5-dependent sensing of endogenous dsRNA and highlight the ADAR1–MDA5-type I interferon axis as a promising therapeutic target for improving immunotherapy in multiple myeloma. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced malignancies. However, only a subset of patients respond to treatment. Recent efforts have focused on the identification of novel biomarkers that capture the dynamic and functional state of the tumour immune microenvironment, yet their clinical translation has remained challenging. Methods: To address these limitations, we applied amplified FRET-FLIM (QF-Pro^®) technology to spatially resolve and quantitatively assess functional immune checkpoint interactions directly in cells and FFPE tissue and tumour samples. Results: Using this approach, we demonstrated that PD-1/PD-L1, CTLA-4/CD80, TIGIT/CD155, and LAG-3/MHC-II interactions can be robustly quantified in routine FFPE patient samples from multiple tumour types. Furthermore, in a proof-of-concept study in a melanoma cohort treated with immune checkpoint inhibitors (ICIs) targeting PD-1 or CTLA-4, co-analysis of all four immune checkpoints suggested patterns of concomitant engagement. Notably, patients with high PD-1/PD-L1 interaction levels tended to also exhibit elevated CTLA-4/CD80 interactions. Survival analysis further showed that high LAG-3/MHC-II interaction status was associated with a trend toward improved overall survival even when corrected for tumour stage, irrespective of the specific ICI regimen administered. Conclusions: Although prospective validation in larger independent cohorts would be critical to establish clinical relevance, these findings support the exploration of LAG-3 engagement as a potential biomarker in melanoma immunotherapy, and more broadly highlight immune checkpoint interaction profiling as a promising avenue to examine in patient stratification. Full article

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine malignancy. Like cutaneous malignant melanomas, a subset of MCCs can clinically present without an identifiable primary tumour, termed Merkel cell carcinoma of unknown primary (UPMCC), with incompletely understood behaviour and prognosis. Our objectives are to evaluate the clinical presentation, management and survival outcomes in UPMCC and compare overall survival with metastatic MCC of known-primary origin. Methods: A retrospective review of 252 consecutive MCC patients (1992–2023) identified 20 cases of histologically confirmed nodal or metastatic UPMCC. Demographics, anatomical distribution, treatment and oncological outcomes were analysed. Overall survival was compared with patients presenting with metastatic MCC of known primary. Results: The cohort included 15 males and 5 females (mean age 76 years). Presentation most commonly involved inguinal (n = 7) and axillary (n = 6) nodes, followed by parotid and cervical basins (n = 4). Management was multimodal, including lymphadenectomy, radiotherapy and systemic therapy. Six patients remained disease-free at a mean follow-up of 63.3 months. The mean overall survival was 43.65 months for UPMCC versus 39.29 months for known-primary metastatic MCC. Conclusions: UPMCC most commonly presents as inguinal or axillary nodal disease. Survival outcomes suggest a trend toward improved prognosis compared to known-primary metastatic MCC. Full article

Background/Aim: Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1–3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well defined. Materials and Methods: A retrospective pan-cancer analysis was performed using the AACR Project GENIE v12 database via cBioPortal. Tumors with somatic FGFR4 mutations were included, excluding copy number alterations and structural variants. Mutations were grouped by hotspot (amino acid 401) and major protein domains. Comparative analyses assessed cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations using chi-square testing with multiple comparison correction. Results: A total of 4565 tumor samples (4283 patients) were analyzed. FGFR4 alterations were observed across diverse malignancies, most commonly non-small cell lung cancer, colorectal cancer, and melanoma. Mutations clustered primarily in the tyrosine kinase and immunoglobulin I-set domains, with no significant variation in distribution across cancer types. Sex was not associated with the mutation group, while race and ethnicity showed significant differences. The FGFR4 hotspot 401 group demonstrated a higher mutation burden, driven by a subset of hypermutated tumors, and showed enrichment for co-occurring alterations in chromatin remodeling, DNA repair, tumor suppressor, and receptor tyrosine kinase genes; however, sensitivity analyses indicated this association was largely attributable to mutation burden rather than a mutation-specific effect. Domain-based mutation groups had lower mutation burdens and fewer co-alterations. Conclusions: FGFR4 alterations occur across a broad range of cancers with consistent domain-level patterns. The hotspot 401 mutation shows a higher mutation burden and co-alteration frequency driven largely by a subset of hypermutated tumors, rather than acting as an isolated driver. Full article

Melanoma is a highly aggressive malignancy characterized by strong invasive and metastatic potential. CPEB4 has been implicated in melanoma progression and may serve as a potential therapeutic target. Alkannin has previously been reported to exert antitumor activity against melanoma; however, its in vivo efficacy and direct molecular interaction with CPEB4 remain unclear. In this study, a subcutaneous xenograft model using BALB/c nude mice was used to assess the in vivo antitumor effects of alkannin, and CPEB4 expression was analyzed via Western blotting. DARTS, CETSA, and SPR investigations were used to elucidate the interaction between alkannin and CPEB4. In addition, stable CPEB4-knockdown A375 melanoma cells were established to examine the effects of alkannin on cell proliferation, apoptosis, cell cycle progression, migration, invasion, and downstream signaling molecules. Alkannin markedly suppressed tumor growth in the xenograft model and reduced CPEB4 expression in a dose-dependent manner compared with the model group. DARTS and CETSA demonstrated alkannin-induced stabilization of CPEB4, while SPR analysis using purified recombinant CPEB4 showed a direct physical interaction with alkannin, with micromolar affinity. At the molecular level, alkannin downregulated CPEB4 and PRC1 expression (p < 0.05), whereas CPEB4 knockdown markedly suppressed MITF and PRC1 (p < 0.05). Notably, alkannin treatment alone did not significantly alter MITF protein expression under the present experimental conditions. Alkannin exerts antitumor activity against melanoma, while its interaction with CPEB4 and the associated molecular changes may contribute to cellular responses involving proliferation, survival, migration, invasion-related phenotypes, and mitotic regulation. Full article