Melanoma Metastasis Research Articles

Unveiling the role of ACTL6A in uveal melanoma metastasis and immune microenvironment.

To predict and evaluate the possible mechanisms and clinical value of ACTL6A in the prognosis and development of UM. Bioinformatics analyze the relationship between ACTL6A and immunity in UM, which derived from TCGA, Gene Expression Omnibus (GEO) databases. Tumor-infltrated immune cells were demonstrated using QUANTISEQ and MCP-counter. Furthermore, scRNA-seq was used to detect ACTL6A expression, distribution, immune infiltration and revealing the gene expression profile of UM. The expression of ACTL6A was lower in UM compared with pantumor in TCGA databases. Kaplan-Meier analysis revealed that downregulated ACTL6A was associated with poor OS, and ACTL6A was associated with cancer stem cells (CSCs) and immune infiltration. Moreover, ACTL6A might act as a chemotherapy resistance gene and closely relate- to epithelial-mesenchymal transition. Analysis in 8 GSE databases showed that IL13, TPTE, IL17B and CCL22 genes were significantly overexpressed in metastatic UM. Furthermore, the single-cell transcriptomic profling identified a new cell cluster - as a unique type of immune cell, which associating with malignant cell heterogeneity and complexity, and further revealing that the metastasis of UM is mainly associated with CD4 Tconv, B , CD8 Tex, and Plasma cells. Downregulated ACTL6A acts as a risk factor for poor prognosis in UM, which implies as an potential prognostic marker for independent targeted immunotherapy.

Steatohepatitis-induced vascular niche alterations promote melanoma metastasis

BackgroundIn malignant melanoma, liver metastases significantly reduce survival, even despite highly effective new therapies. Given the increase in metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), this study investigated the impact of liver sinusoidal endothelial cell (LSEC)-specific alterations in MASLD/MASH on hepatic melanoma metastasis.MethodsMice were fed a choline-deficient L-amino acid-defined (CDAA) diet for ten weeks to induce MASH-associated liver fibrosis, or a CDAA diet or a high fat diet (HFD) for shorter periods of time to induce early steatosis-associated alterations. Liver metastasis formation was assessed using melanoma cell lines B16F10Luc2 and Wt31. LSEC-specific GATA4 knockout mice (Gata4LSEC−KO/BL) developing MASH-like liver fibrosis without steatosis via a pathogenic angiocrine switch were included to compare the impact of liver fibrosis versus hepatic steatosis on hepatic melanoma metastasis. Bulk RNA-Seq of isolated LSECs from CDAA-fed and control mice was performed. Levels of adhesion molecules (VCAM1, ICAM1, E-selectin) were monitored, and ICAM1 and VCAM1 antibody therapy was employed.ResultsFeeding a CDAA diet, in contrast to a HFD, led to increased metastasis before the development of liver fibrosis. Gata4LSEC−KO/BL mice characterized by vascular changes ensuing perisinusoidal liver fibrosis without steatosis also exhibited increased metastasis. Early molecular alterations in the hepatic vascular niche, rather than fibrosis or steatosis, correlated with metastasis, as shown by LSEC dedifferentiation and upregulation of endothelial adhesion molecules. The metastatic process in CDAA-fed mice was also dependent on the respective melanoma cell lines used and on the route of their metastatic spread. ICAM1 inhibition, but not VCAM1 inhibition reduced melanoma cell retention.ConclusionWe discovered that the hepatic vascular niche acts as a delicate sensor to even short-term nutritional alterations during the development of MASLD/MASH. The dynamic adaptations to the metabolic challenges of developing MASLD/MASH caused an early shift from the normal hepatic vascular niche to a pre-metastatic vascular niche that promoted hepatic melanoma metastasis in the context of cell-autonomous and acquired melanoma cell features. Altogether, our findings provide a potential avenue for angiotargeted therapies to prevent hepatic melanoma metastasis.

HDAC3 and Snail2 complex promotes melanoma metastasis by epigenetic repression of IGFBP3.

The treatment of metastatic melanoma has long posed a complex challenge within clinical practice. Previous studies have found that EMT transcription factors are essential in the development of various cancers through their induction of EMT. Here, we demonstrate that Snail2 expression is dramatically increased in melanoma and is associated with an adverse prognosis. Elevated Snail2 in melanoma cells enhanced migratory and invasive capabilities in vitro and in vivo. Furthermore, RNA-Seq analysis revealed a significant reduction of IGFBP3 expression in melanoma cells overexpressing Snail2. IGFBP3 might mitigate the Snail2's ability to promote melanoma metastasis via the PI3K-AKT pathway. Moreover, Snail2 and HDAC3 collaborate to suppress IGFBP3 transcription through H3K4 deacetylation and H4K5 delactylation. Additionally, the combination of HDAC3 and p-GSK-3β inhibitors significantly improved the treatment outcomes for lung metastasis in melanoma in vivo. The results of our study indicate that Snail2, HDAC3, and IGFBP3 play significant roles in melanoma progression and represent promising therapeutic targets.

Melanoma-derived cytokines and extracellular vesicles are interlinked with macrophage immunosuppression

Cytokines play a crucial role in mediating cell communication within the tumor microenvironment (TME). Tumor-associated macrophages are particularly influential in the regulation of immunosuppressive cytokines, thereby supporting tumor metastasis. The upregulation of Th2 cytokines in cancer cells is recognized for its involvement in suppressing anticancer immunity. However, the association between these cytokines and tumor-secreted extracellular vesicles (EVs) remains poorly understood. Therefore, our objective was to investigate the connection between tumor-promoting macrophages and melanoma-derived EVs. The analysis from altered cytokine profile data showed that melanoma-derived EVs upregulate Th2 cytokine expression in naïve macrophages, thereby contributing to the promotion of tumor-supporting functions. Notably, many of these cytokines were also found to be upregulated in metastatic melanoma patients (n = 30) compared to healthy controls (n = 33). Overall, our findings suggest a strong connection between melanoma secretory EVs and the induction of tumor-associated macrophages that facilitates the development of an immunosuppressive TME, supporting melanoma metastasis through regulation at both local and systemic levels.

Selective expression and significance of ACKR2 in lung aerocytes

BackgroundACKR2 is an atypical chemokine receptor that plays a significant role in regulating inflammation by binding to inflammatory CC chemokines and facilitating their degradation. Previous findings suggest that the genetic...

Inhibition of programmed cell death by melanoma cell subpopulations reveals mechanisms of melanoma metastasis and potential therapeutic targets

Melanoma is an aggressive type of skin cancer that arises from melanocytes, the cells responsible for producing skin pigment. In contrast to non-melanoma skin cancers like basal cell carcinoma and squamous cell carcinoma, melanoma is more invasive. Melanoma was distinguished by its rapid progression, high metastatic potential, and significant resistance to conventional therapies. Although it accounted for a small proportion of skin cancer cases, melanoma accounts for the majority of deaths caused by skin cancer due to its ability to invade deep tissues, adapt to diverse microenvironments, and evade immune responses. These unique features highlighted the challenges of treating melanoma and underscored the importance of advanced tools, such as single-cell sequencing, to unravel its biology and develop personalized therapeutic strategies. Thus, we conducted a single-cell analysis of the cellular composition within melanoma tumor tissues and further subdivided melanoma cells into subpopulations. Through analyzing metabolic pathways, stemness genes, and transcription factors (TFs) among cells in different phases (G1, G2/M, and S) as well as between primary and metastatic foci cells, we investigated the specific mechanisms underlying melanoma metastasis. We also revisited the cellular stemness and temporal trajectories of melanoma cell subpopulations, identifying the core subpopulation as C0 SOD3 + Melanoma cells. Our findings revealed a close relationship between the pivotal C0 SOD3 + Melanoma cells subpopulation and oxidative pathways in metastatic tumor tissues. Additionally, we analyzed prognostically relevant differentially expressed genes (DEGs) within the C0 SOD3 + Melanoma cells subpopulation and built a predictive model associated with melanoma outcomes. We selected the gene IGF1 with the highest coefficient (coef) value for further analysis, and experimentally validated its essential function in the proliferation and invasive metastasis of melanoma. In immune infiltration analysis, we discovered the critical roles played by M1/M2 macrophages in melanoma progression and immune evasion. Furthermore, the development and progression of malignant melanoma were closely associated with various forms of programmed cell death (PCD), including apoptosis, autophagic cell death, ferroptosis, and pyroptosis. Melanoma cells often resisted cell death mechanisms, maintaining their growth by inhibiting apoptosis and evading autophagic cell death. Meanwhile, the induction of ferroptosis and pyroptosis was thought to trigger immune responses that helped suppress melanoma dissemination. A deeper understanding of the relationship between melanoma and PCD pathways provided a critical foundation for developing novel targeted therapies, with the potential to enhance melanoma treatment efficacy. These findings contributed to the development of novel prognostic models for melanoma and shed light on research directions concerning melanoma metastasis mechanisms and therapeutic targets.

Posterior Fossa Stereotactic Biopsy with Leksell Vantage Frame-Case Series and Review of Literature.

Background: Stereotactic biopsy of posterior fossa lesions, which are often inoperable, enables a safe trajectory and provides tissue samples for accurate diagnosis, which is crucial for correct treatment since the latest World Health Organization Classification of Tumors of the Central Nervous System from 2021 places immense emphasis on molecular diagnostics. Stereotactic biopsy using the Leksell Vantage headframe is, due to its rigid design, extremely accurate, but stiffer, making the procedure more challenging and the learning curve steeper. Methods: This retrospective analysis demonstrates the introduction of the new Leksell Vantage headframe in day-to-day practice at the University Medical Center in Maribor, Slovenia, in demanding procedures of posterior fossa biopsies, and also provides a review of the literature available on the topic with emphasis on the technical aspect of posterior fossa biopsy using the Leksell Vantage headframe in adults. Results: In the observed series of three patients with posterior fossa lesions, all biopsies were representative, despite tissue samples being small, providing conclusive histopathologic reports (glioblastoma, rosette-forming glioneuronal tumor and metastasis of melanoma) with additional molecular diagnostics. After the initial biopsy case, the preoperative planning times and procedure times were shortened as we learnt about the importance of a tailored approach from the first case. In all cases, the biopsy was performed under local anesthesia with patients being awake throughout surgery. Conclusions: The rigid Leksell Vantage headframe makes access to the posterior fossa tougher when compared to its predecessors. However, the procedure is very accurate but requires precise preoperative planning and a customized approach when placing the headframe.

Cryoshocked Adipocytes Mediated Dual-Modal Strategy Combining Photodynamic Therapy and Triptolide Palmitate for Pulmonary Metastatic Melanoma Treatment.

Pulmonary metastasis represents one of the most prevalent forms of metastasis in advanced melanoma, with mortality rates reaching 70%. Current treatments including chemotherapy, targeted therapy, and immunotherapy frequently exhibit limited efficacy or present high costs. To address these clinical needs, this study presents a biomimetic drug delivery system (Ce6-pTP-CsA) utilizing cryoshocked adipocytes (CsA) encapsulating the prodrug triptolide palmitate (pTP) and the photosensitizer Ce6, exploiting the characteristic of tumor cells to recruit and lipolyze adipocytes for energy. CsA substantially enhances the drug-loading capacity of adipocytes, with its particle size characteristics enabling targeted delivery of pTP to the lungs. The combination of photodynamic therapy (PDT) and pTP activates the caspase cascade, promoting apoptosis in tumor cells. Notably, the cleavage of disulfide bonds in pTP depletes glutathione (GSH), reducing its scavenging effect on reactive oxygen species (ROS) and enhancing the efficacy of PDT. Results demonstrate that Ce6-pTP-CsA effectively inhibits the proliferation and invasion of pulmonary metastatic melanoma cells in vitro and induces apoptosis, while significantly suppressing lung metastasis of SCID mice models in vivo. In conclusion, this novel biomimetic drug delivery system based on adipocytes provides a promising strategy for targeted therapy in pulmonary metastatic melanoma.

Generation of a genetically engineered porcine melanoma model featuring oncogenic control through conditional Cre recombination

Melanoma is a serious type of skin cancer that originates from melanocytes. Rodent melanoma models have provided valuable insights into melanoma pathology; however, they often lack applicability to humans owing to genetic, anatomical, physiological, and metabolic differences. Herein, we developed a transgenic porcine melanoma model that closely resembles humans via somatic cell nuclear transfer (SCNT). Our model features the conditional oncogenes cassettes, TP53R167H and human BRAFV600E, controlled by melanocyte-specific CreER recombinase. After SCNT, transgenic embryos developed normally, with the capacity to develop porcine embryonic stem cells. Seven transgenic piglets with oncogene cassettes were born through embryo transfer. We demonstrated that Cre recombination-mediated oncogene activation remarkably triggered the mitogen-activated protein kinase pathway in vitro. Notably, intradermal injection of 4-hydroxytamoxifen activated oncogene cassettes in vivo, resulting in melanocytic lesions resembling hyperpigmented nevi with increased proliferative properties similar to early human melanomas. This melanoma-inducing system, heritably transmitted to offspring, supports large-scale studies. The novel porcine model provides a valuable tool for elucidating melanoma development and metastasis mechanism, advancing translational medicine, and facilitating preclinical evaluation of new anticancer drugs.

Targeting Angiogenesis: New Horizons in Ocular Tumor Therapy

Angiogenesis, the formation of new blood vessels within malignant tumors, is essential for cancer growth, sustenance, and metastasis. This complex process is regulated by a variety of molecular factors and pathways, as explored in a recent comprehensive review on angiogenesis. The review highlights the regulatory mechanisms that unlock therapeutic potential, focusing on hypoxia and its role in inducing vascular endothelial growth factor (VEGF) expression, a key driver of angiogenesis. It examines the interplay between angiopoietins, fibroblast growth factors (FGFs), and endogenous inhibitors of angiogenesis, as well as the role of transmembrane adhesion proteins, such as integrins, in mediating cellular responses critical to vascular development. The review also discusses the critical role of angiogenesis in tumor growth, emphasizing how the "angiogenic switch" enables tumors to acquire an aggressive phenotype. In this context, anti-angiogenic (AAG) therapies targeting these pathways are being investigated for various cancers, including ocular malignancies. Despite the widespread use of angiogenesis inhibitors in non-malignant ocular diseases, reports of their application in ocular tumors remain limited. Evidence supports the involvement of angiogenesis in the progression and metastasis of ocular malignancies, including retinoblastoma, ocular melanoma, and Von Hippel-Lindau (VHL) disease. Preliminary studies of AAG therapies for ocular tumors, such as ocular melanoma and VHL, show promising results. However, their efficacy needs to be confirmed through well-designed, controlled clinical trials. By providing a detailed overview of the molecular underpinnings of angiogenesis and its implications for tumor growth, this review underscores the potential of targeting angiogenic pathways as a therapeutic strategy for ocular tumors and other malignancies.

Decavanadate Compound Displays In Vitro and In Vivo Antitumor Effect on Melanoma Models.

The efficacy of available treatments for melanoma is limited by side effects and the rapidly emerging resistance to treatment. In this context, the decavanadate compounds represent promising tools to design efficient therapeutic agents. In our study, we synthesized a dimagnesium disodium decavanadate icosahydrate compound (Mg2Na2V10O28·20H2O) and investigated its structure stability as well as its antimelanoma effects. Results showed that the Mg2Na2V10O28·20H2O compound is structured in a monoclinic system with the space group C2/c, stabilized by oxygen vertices, hydrogen bonds, and van der Waals interactions. Interestingly, we found that this newly synthesized compound reduced the viability of human (IGR39, IGR37, and SKMEL28) and murine (B16-F10) melanoma cells in a dose-dependent manner. The IC50 values ranged from 7.3 to 18 μM after 24 h and decreased to 1.4 μM after 72 h of treatment. Notably, this effect was more important than that of cisplatin (IC50 = 3 μM after 72 h of treatment), a chemotherapeutic agent, commonly used in the treatment of malignant melanoma. Furthermore, the cytotoxicity of the decavanadate compound was relatively weak on normal human keratinocytes (HaCaT), with a light effect (IC50 >> 70 μM) observed after 24 h of treatment. Thus, the Mg2Na2V10O28·20H2O compound displayed an advantage over cisplatin, which was reported to be much more aggressive to the keratinocyte cell line (IC50 = 23.9 μM). Moreover, it inhibited dose-dependently the adhesion of IGR39 cells to collagen (IC50 = 2.67 μM) and fibronectin, as well as their migration with an IC50 value of 2.23 μM. More interestingly, its in vivo administration to B16-F10 allografted mice, at the nontoxic dose of 50 μg (2.5 mg/kg), prevented and suppressed by 70% the tumor growth, compared to the nontreated mice. Moreover, this compound has also allowed a recovery against inflammation induced in mice by a mixture of DMBA and croton oil. Thus, all our results showed the potential of the Mg2Na2V10O28·20H2O compound to prevent and efficiently treat the growth and metastasis of melanoma.

Studying the role of thrombomodulin-plasminogen interaction in spatial and interfacial invasion of melanoma metastatic progression

Thrombomodulin (TM), a transmembrane glycoprotein, has emerged as a key factor in the metastatic spread of various cancers, including malignant melanoma. Despite its recognized significance, the underlying mechanisms of TM's involvement in enhancing metastasis remain incompletely understood. This study addresses this knowledge gap by utilizing spatial and interfacial invasion models in vitro to investigate the effect of the interaction between TM and plasminogen (Plg) on melanoma invasion. While it is well established that Plg induces a chain reaction in the plasmin system, leading to the activation of metalloproteases that promote tumor cell invasion and metastasis, this study is the first to demonstrate that TM binding to Plg can enhance these activations in spatial and interfacial invasion models in vitro. These results highlight the potential of TM as a crucial target for the development of drugs aimed at significantly inhibiting melanoma metastasis and improving patient survival.

Basophil-Derived IL-4 Production and Its Potential Pro-Tumoural Role in Th2-Polarisation Within Sentinel Lymph Nodes of Primary Cutaneous Melanoma.

Chronic inflammation in the tumour microenvironment (TME) via Th2-polarisation promotes melanoma progression and metastasis, making it a target for immunotherapy. Interleukin (IL)-4 is considered essential for Th2-polarisation in the TME; however, its source remains unknown. Basophils have been postulated as one of its sources. Basophil-derived IL-4 contributes to Th2-polarisation in parasitic infections and allergic diseases and has been implicated in tumour immunity. To identify basophil infiltration into the TME of human melanoma skin lesions and sentinel lymph nodes (SLNs) and demonstrate that basophils produce IL-4. Immunohistochemistry (IHC) with a basophil-specific BB1 antibody and insitu hybridisation. Basophils tended to infiltrate skin lesions at Stage II or later. Higher numbers of infiltrating basophils correlated with the Breslow depth and a shorter progression-free survival, indicating an association with poor prognosis. In SLNs, basophils infiltrated at early stages without metastasis (Stages I and II), with the number of infiltrating basophils being significantly higher in Stage II than in Stage I. IHC revealed that IL-4 levels were also significantly elevated in Stage II SLNs compared to Stage I SLNs. Furthermore, a positive correlation was observed between the number of basophils infiltrating SLNs and IL-4 expression. Insitu hybridisation confirmed that basophils expressed IL4. These findings are consistent with previous reports of early-stage melanoma SLNs having a Th2-environment and suggest that basophil-derived IL-4 may contribute to a metastasis-promoting environment in SLNs through Th2-polarisation. Basophils may represent potential immunotherapeutic targets for pro-tumour changes that occur in SLNs in early-stage melanoma.

Deficiency of myeloid discoidin domain receptor 2 aggravates melanoma lung and bone metastasis.

Melanoma, one of the most prevalent cancers worldwide, frequently metastasizes to the lung and bones. Tumor-associated macrophages play essential roles in melanoma metastasis but the underlying mechanism remains obscure. We previously demonstrated that specific knockout of Ddr2, a receptor tyrosine kinase, exacerbates systemic inflammation via modulating macrophage repolarization. To investigate whether myeloid Ddr2 regulates melanoma growth and metastasis, we injected B16BL6 melanoma cells into Ddr2LysM (cKO) mice via subcutaneous neck, tail vein, and left ventricle, respectively. We found that the growth of melanoma cells in cKO mice was significantly retarded, as demonstrated by the subcutaneous transplantation tumor model. Unexpectedly, the melanoma metastasis to the lung or bone was significantly stimulated in cKO mice, indicating the complicated role of Ddr2 in macrophages in melanoma development. Furthermore, Ddr2 in macrophages regulated the migration of B16BL6 cells in the co-culture system. Bioinformatics analysis showed that Ddr2 expression correlates with improved prognostic outcomes in melanoma, and high expression of Ddr2 is protective in melanoma metastasis. Our results enrich the current knowledge of Ddr2 in tumor biology and indicate that more consideration should be taken when applying Ddr2 inhibition as a melanoma treatment strategy.

MLLT3 Regulates Melanoma Stemness and Progression by Inhibiting HMGB1 Nuclear Entry and MAGEA1 M5C Modification

AbstractMelanoma stem cells are a kind of cells with self‐renewal and multi‐directional differentiation potential. They are one of the key factors in the occurrence, development and metastasis of melanoma. This study demonstrates that MLLT3 is a transcription factor that regulates the stemness and progression of melanoma. MLLT3 interacted with HMGB1 to inhibit its entry into the nucleus, MLLT3 interacted with YBX1 to inhibit its reading of m5C of MAGEA1, thereby inhibiting the mRNA stability of MAGEA1, and directly transcribed P53 to inhibit the stemness, proliferation and metastasis of melanoma cells. This study further explored the potential mechanism of the interaction between miR‐542‐3p/miR‐3922‐3p and MLLT3. Furthermore, the scRNA‐seq of melanoma cells with MLLT3 knock‐out resulted in important changes in cell subsets, activating the TP53 and MAPK pathways and transforming into stem cells. The results indicate that the transcription factor MLLT3 is a suppressor gene that regulates the stemness and progression of melanoma, and is expected to become a target for melanoma therapy.

New Axes of Interaction in Circ_0079593/miR-516b-5p Network in Melanoma Metastasis Cell Lines.

microRNAs (miRNAs) and circular RNA (circRNAs) show a close interconnection in the control of fundamental functions, such as cell proliferation and tumor development. A full understanding of this complex and interconnected network is essential for better understanding the mechanisms underlying cancer progression. Hsa_circ_0079593 is a circRNA highly expressed in melanoma and is associated with increased metastasis and progression of malignancy, whereas miR516b-5p is a microRNA whose expression is lower in several tumor types, including melanoma; its overexpression inhibits cell proliferation, migration, and invasion. In this study, we tested whether circ_0079593 is involved in the progression of melanoma aggressiveness by regulating CHAF1B and MCAM via the inhibition of miR-516b-5p. We first verified the expression of the key components in both healthy melanocyte lines and melanoma metastases, subsequently using in vitro assays such as scratch tests, Western blot, qRT-PCR, and dual luciferase report assay; we verified their interconnected regulatory effect. Our results showed that circ_0079593-miR516b-5p interactions are involved in the increase in the migration of metastasis melanoma cells by exploiting their binding to MCAM and CHAF1B mRNAs. This study provides two other regulatory networks in which circ_0079593 may exert its oncogenic function by increasing the speed of movement of metastatic cells through the sponge of miR-516b-5p, which cannot regulate MCAM and CHAF1B expression.

Metabolic insights into tumor lymph node metastasis in melanoma.

Although accounting for only a small amount of skin cancers, melanoma contributes prominently to skin cancer-related deaths, which are mostly caused by metastatic diseases, and lymphatic metastasis constitutes the main route. In this review, we concentrate on the metabolic mechanisms of tumor lymph node (LN) metastasis in melanoma. Two hypotheses of melanoma LN metastasis are introduced, which are the premetastatic niche (PMN) and parallel progression model. Dysregulation of oxidative stress, lactic acid concentration, fatty acid synthesis, amino acid metabolism, autophagy, and ferroptosis construct the metabolic mechanisms in LN metastasis of melanoma. Moreover, melanoma cells also promote LN metastasis by interacting with non-tumor cells through metabolic reprogramming in TIME. This review will deepen our understanding of the mechanism of lymph node metastasis in melanoma.

Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.

Association Between Melanoma Metastasis and Metabolic Syndrome: A Cross-Sectional Study in a Chinese Population.

Metabolic syndrome (MetS) remains a significant global public health concern. However, the relationship between MetS, its individual components and melanoma metastasis remains unexplored. We analysed the clinical data of 258 Chinese melanoma patients who had not undergo systemic therapy. Binary logistic regression, adjusted for sex and age, was employed to evaluate the connection between MetS and its components and melanoma metastasis. Of the 258 melanoma patients, 92 met the MetS criteria upon diagnosis. No direct association between MetS and melanoma metastasis was identified. However, specific components of MetS, namely low HDL-cholesterol levels (OR = 2.85, 95% CI:1.50-5.41, p < 0.05) and dysglycaemia (OR = 4.23, 95% CI:1.80-8.96, p < 0.05), were associated with melanoma metastasis. In subgroup analysis, hypertriglyceridemia correlated with melanoma metastasis in non-elderly patients (< 65 years) (OR = 2.69, 95% CI: 1.14-6.33, p < 0.05). Central obesity and hypertension showed no association. A dose-response analysis further indicated that melanoma metastasis risk escalated with increasing fasting blood glucose and blood triglyceride concentrations, and with decreasing blood HDL concentration. Our results suggest that monitoring and managing individual components of the MetS, particularly HDL-cholesterol levels, fasting glucose and triglyceride levels, may have potential prognostic benefits for melanoma in the Chinese population.

A Pioneer Review on Lactoferrin-Conjugated Extracellular Nanovesicles for Targeting Cellular Melanoma: Recent Advancements and Future Prospects.

Melanoma, a highly aggressive form of skin cancer, presents a formidable challenge in terms of treatment due to its propensity for metastasis and resistance to conventional therapies. The development of innovative nanocarriers for targeted drug delivery has opened new avenues in cancer therapy. Lactoferrin-conjugated extracellular nanovesicles (LF-EVs) have emerged as a promising vehicle in the targeted treatment of cellular melanoma, owing to their natural biocompatibility, enhanced bioavailability, and ability to traverse biological barriers effectively. This review synthesizes recent advancements in the use of LF-EVs as a novel drug delivery system for melanoma, emphasizing their unique capacity to enhance cellular uptake through LF's receptor-mediated endocytosis pathways. Key studies demonstrate that LF conjugation significantly increases the specificity of extracellular nanovesicles for melanoma cells, minimizes off-target effects, and promotes efficient intracellular drug release. Furthermore, we explore how LF-EVs interact with the tumor microenvironment, potentially inhibiting melanoma progression and metastasis while supporting antitumor immune responses. Future prospects in this field include optimizing LF conjugation techniques, improving the scalability of LF-EV production, and integrating multifunctional payloads to target drug resistance mechanisms. This review highlights the potential of LF-EVs to transform melanoma treatment strategies, bridging current gaps in therapeutic delivery and paving the way for personalized and less invasive melanoma therapies.