Single-Cell Transcriptomic Landscape Deciphers Intratumoral Heterogeneity and Subtypes of Acral and Mucosal Melanomas

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Acral melanoma (AM) and mucosal melanoma (MM) are rare but aggressive subtypes of cutaneous melanoma.
• Understanding their distinct intratumoral and microenvironmental heterogeneity is crucial for developing effective therapies.

Purpose of the Study:

• To delineate the distinct cellular compositions and evolutionary trajectories of AM and MM.
• To identify subtype-specific therapeutic strategies for these melanomas.

Main Methods:

• Single-cell RNA sequencing and whole-exome sequencing were performed on 42 melanoma samples (28 AM, 11 MM).
• Functional assays including transwell migration, co-culture systems, and xenograft models were utilized for validation.
• Tumor and stromal cells were profiled to analyze cellular and molecular characteristics.

Main Results:

• MM showed high epithelial-to-mesenchymal transition potential, neutrophil infiltration, and CXCL3+ macrophages.
• AM was enriched with PI16+ cancer-associated fibroblasts and TIGIT+ regulatory T cells.
• MM subtypes were identified: antigen-presenting (favorable outcome) and proliferative (recurrence).
• BRAF/NRAS mutations were linked to ALDOA+ stem-like cells, and prostaglandin D2 synthetase emerged as a therapeutic target.

Conclusions:

• This study provides a comprehensive comparison of AM and MM, revealing subtype-specific stromal-immune interactions.
• Actionable targets like TIGIT in AM and CXCL3+ macrophages in MM were highlighted.
• A framework for precision therapies, biomarker-driven trials, and risk stratification was proposed to improve outcomes.