Single-Nuclei Transcriptome Profiling Reveals Intra-Tumoral Heterogeneity and Characterizes Tumor Microenvironment...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Malignant melanoma is an aggressive cancer with high metastasis and mortality.
• Cancer cell heterogeneity and the tumor microenvironment (TME) are key challenges in melanoma research.
• Single-cell RNA sequencing (scRNA-seq) is powerful but limited by dissociation-induced stress; single nucleus RNA sequencing (snRNA-seq) offers advantages like frozen sample compatibility and avoiding this stress.

Purpose of the Study:

• To profile and understand the functional diversity of cellular components during melanoma progression.
• To investigate intratumor heterogeneity and dynamics using snRNA-seq in a murine melanoma model.
• To identify potential new biomarkers within the TME for therapeutic targeting.

Main Methods:

• Performed snRNA-seq on 16,839 nuclei from murine syngeneic melanoma models.
• Samples were collected at 9 and 23 days post-subcutaneous injection, representing early and advanced tumor growth stages.
• Utilized a BRAFV600E mutated murine melanoma model.

Main Results:

• Defined 11 distinct subtypes of malignant cell clusters.
• Identified 5 different subsets of myeloid cells with unique transcriptional programs.
• Observed differential enrichment of cell subsets in early versus advanced tumor stages, confirming intratumor heterogeneity and dynamics.
• Demonstrated snRNA-seq's utility in accurately identifying these features.

Conclusions:

• snRNA-seq provides deep insights into melanoma biology and TME reprogramming during tumor evolution.
• The study highlights the dynamic nature of the TME in melanoma progression.
• Findings suggest potential for discovering novel, druggable TME biomarkers.