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

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

Publication date: Jan 20, 2025

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.

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Concepts Keywords
Carcinoma Macrophages
Discov Melanoma
Light Oxidative phosphorylation
Melanocytes Programmed cell death
Microenvironments Single-cell RNA sequencing
Tumor metastasis

Semantics

Type Source Name
disease MESH melanoma
pathway KEGG Melanoma
disease MESH metastasis
disease MESH skin cancer
disease MESH basal cell carcinoma
pathway KEGG Basal cell carcinoma
disease MESH squamous cell carcinoma
disease MESH tumor
pathway KEGG Metabolic pathways
drug DRUGBANK Mecasermin
pathway REACTOME Programmed Cell Death
pathway REACTOME Apoptosis
pathway KEGG Ferroptosis
pathway REACTOME Pyroptosis
disease MESH death
disease MESH carcinoma
drug DRUGBANK Coenzyme M
disease MESH noma
pathway KEGG Oxidative phosphorylation
disease MESH relapse
disease MESH inflammation
drug DRUGBANK Isoxaflutole
drug DRUGBANK Oxygen
pathway REACTOME Metabolism
drug DRUGBANK Pidolic Acid
drug DRUGBANK Saquinavir
drug DRUGBANK Stavudine
drug DRUGBANK Streptomycin
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Glycine
drug DRUGBANK Gentian violet cation
pathway REACTOME M Phase
drug DRUGBANK Honey
disease MESH tic
pathway KEGG Glutathione metabolism
pathway REACTOME Glycolysis
pathway REACTOME Gluconeogenesis
pathway REACTOME Extracellular matrix organization
disease MESH tissue adhesion
drug DRUGBANK Myricetin
disease MESH gastric cancer
pathway KEGG Gastric cancer
drug DRUGBANK Trestolone
pathway REACTOME Keratinization
disease MESH infection
drug DRUGBANK Proline
drug DRUGBANK Activated charcoal
disease MESH breast cancer
pathway KEGG Breast cancer
disease MESH lung cancer
drug DRUGBANK Hyaluronic acid
disease MESH hypoxia
disease MESH Wilms tumor
disease MESH colorectal cancer
pathway KEGG Colorectal cancer
disease MESH Clinical relevance
disease MESH tumor escape
pathway REACTOME Autophagy
pathway REACTOME Immune System
disease MESH oxidative stress
pathway REACTOME Reproduction
drug DRUGBANK Bismuth subgallate
disease MESH Uveal melanoma
disease MESH glioma
pathway KEGG Glioma
drug DRUGBANK L-Aspartic Acid
pathway REACTOME Mitochondrial biogenesis
disease MESH multiple myeloma
drug DRUGBANK Capsaicin
disease MESH endometrial carcinoma
disease MESH ovarian cancer
pathway REACTOME Sphingolipid metabolism
disease MESH neuroblastoma
disease MESH cardiomyopathy
disease MESH postmenopausal osteoporosis
disease MESH neuroinflammation
disease MESH demyelination
pathway REACTOME Methylation
disease MESH hepatocellular carcinoma
pathway KEGG Hepatocellular carcinoma
disease MESH renal carcinomas
disease MESH glioblastoma
pathway KEGG Necroptosis
disease MESH adenocarcinoma
drug DRUGBANK Methylergometrine
pathway KEGG Endometrial cancer
drug DRUGBANK Carboxyamidotriazole
disease MESH arthritis
drug DRUGBANK Clarithromycin
drug DRUGBANK Levofloxacin
disease MESH Oncogenesis
pathway REACTOME Vitamins
pathway KEGG Peroxisome
drug DRUGBANK Cisplatin
drug DRUGBANK ANX-510
drug DRUGBANK Guanosine
disease MESH Obesity
disease MESH hypertension
pathway KEGG Phagosome

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