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Updated: Jan 9, 2026
Patient Derived Cell Culture and Isolation of CD133+ Putative Cancer Stem Cells from Melanoma
Published on: March 13, 2013
CD33 drives cutaneous melanoma: mendelian randomization confirms causality, multi-omics and in vitro experiments
Longyuan Hu1,2, Yapeng Wang2,3, Limin Liu4
1Medical Experimental Research Center, Guilin Hospital of the Second Xiangya Hospital, Central South University, Guilin, Guangxi, China.
Background:
Cutaneous melanoma (CM), one of the most prevalent types of melanomas globally, continues to increase in incidence and mortality. Despite significant advances in targeted and immune therapies, most patients fail to achieve durable response; high rates of immune resistant and recurrence underscore the urgent need for novel therapeutic targets to improve prognosis and treatment outcomes.
Materials And Methods:
Mendelian randomization (MR), summary-data-based MR (SMR) and colocalization analyses were employed to explore potential drug targets of CM via summary data from FinnGen cohorts (melanoma of skin: nCase = 3194, nControl = 314 193; melanoma in situ: nCase = 980, nControl = 313 899; melanoma of uvea: nCase = 293, nControl = 345 118), 731 immune cell traits (N = 3757) from the GWAS Catalog and protein quantitative trait loci (pQTL) in plasma from the deCODE genetics database. Bulk transcriptomes from the TCGA, GTEx and GENT2 databases, as well as single-cell transcriptomes from the GEO DataSets and published datasets, were analyzed to uncover potential mechanisms of CM development, which were then validated by in vitro experiments.
Results:
Eight immune cell traits were positively related with both melanoma of skin and melanoma in situ, among these, six traits were CD33 mean fluorescence intensity (MFI) on immune cells. MR analysis of CD33 cis-pQTL also showed positive correlation and cis-pQTL data of CD33 pass SMR and HEIDI test both in melanoma of skin and melanoma in situ. The causal relationship between CD33, immune cell traits and cutaneous melanoma was further verified by colocalization analysis with a medium degree of confidence. Analysis of bulk transcriptome and single-cell transcriptome data revealed that CD33, which is mainly expresses on Macrophage/Dendritic cells in the tumor microenvironment (TME) of cutaneous melanoma, related with M2 macrophages differentiation. The results of in vitro experiments demonstrated that CD33 downregulation could inhibit M2 macrophages polarization, and decreased CD33 expression on M2 macrophages could inhibit proliferation and migration of melanoma cells.
Conclusion:
By integrating MR, multi-omics transcriptome analysis and in vitro experiments validation, the present study revealed that CD33 could facilitate CM development by promoting M2 macrophages polarization.
Insights
This study identifies CD33 as a key factor in cutaneous melanoma (CM) development. Targeting CD33 may inhibit M2 macrophage polarization, offering a potential new therapeutic strategy for melanoma.
Area of Science:
- Immunology
- Genetics
- Oncology
Background:
- Cutaneous melanoma (CM) incidence and mortality are rising globally.
- Current targeted and immune therapies offer limited durable responses, highlighting the need for new therapeutic targets.
- High rates of immune resistance and recurrence in CM necessitate novel treatment strategies.
Purpose of the Study:
- To identify potential drug targets for cutaneous melanoma (CM).
- To explore the role of CD33 in CM development and progression.
- To investigate the relationship between CD33, immune cell traits, and melanoma.
Main Methods:
- Mendelian randomization (MR), summary-data-based MR (SMR), and colocalization analyses were performed using large-scale genetic and immune cell trait data.
- Bulk and single-cell transcriptomic data from multiple databases were analyzed to understand CM mechanisms.
- In vitro experiments were conducted to validate the functional role of CD33 in melanoma cells and macrophages.
Main Results:
- Eight immune cell traits, including CD33 mean fluorescence intensity (MFI), were positively associated with both skin and in situ melanoma.
- MR and colocalization analyses supported a causal relationship between CD33, immune cell traits, and CM.
- CD33 expression in the tumor microenvironment correlated with M2 macrophage differentiation; downregulating CD33 inhibited M2 polarization and melanoma cell proliferation/migration.
Conclusions:
- CD33 promotes cutaneous melanoma (CM) development by enhancing M2 macrophage polarization.
- The findings suggest CD33 as a potential therapeutic target for CM.
- Integrated multi-omics and experimental validation provide strong evidence for CD33's role in CM pathogenesis.
