Endothelial cell-specific DNA methylation alterations in breast cancer

Area of Science:

• Epigenetics
• Cancer Biology
• Tumor Microenvironment

Background:

• DNA methylation alterations are key in cancer development.
• Cell-specific methylation patterns within the tumor microenvironment (TME) remain poorly understood.
• Single-cell DNA methylation profiling in the TME faces technical and cost limitations.

Purpose of the Study:

• To computationally infer lineage-specific epigenetic alterations in the TME using bulk DNA methylation data.
• To investigate DNA methylation differences in tumor endothelial cells (TECs) compared to non-tumor endothelial cells.
• To identify TEC-specific methylation changes and their potential role in cancer angiogenesis and vascular dysfunction.

Main Methods:

• Utilized bulk DNA methylation data from large discovery and validation cohorts (n=1071 tumor, n=415 non-tumor).
• Employed cell type deconvolution (HiTIMED) and an interaction testing framework (CellDMC).
• Integrated findings with gene expression data and orthogonal data sources for validation.

Main Results:

• >4500 tumor endothelial cell (TEC)-specific CpGs with altered DNA methylation were identified and validated.
• Many altered CpGs mapped to genes critical for angiogenesis and endothelial function.
• TEC-specific methylation alterations were linked to potential reprogramming of transcriptional networks controlling angiogenesis.

Conclusions:

• High-resolution, cell lineage-specific epigenetic landscapes can be inferred from bulk methylation data.
• TEC-specific DNA methylation alterations are implicated as potential drivers of cancer angiogenesis and vascular dysfunction.
• This study provides a framework for future mechanistic and translational research on tumor vasculature.