Spatial Chromatin Accessibility Analysis of Intratumor Heterogeneity in Breast Cancer

Area of Science:

• Genomics and Epigenetics
• Cancer Biology
• Immunology

Background:

• Intratumoral heterogeneity (ITH) is a key driver of breast cancer (BC) mortality and treatment variability.
• Understanding ITH mechanisms is crucial for advancing BC research and patient outcomes.
• Chromatin accessibility is vital for gene regulation, cellular identity, and tumor evolution, but challenging to study in situ.

Purpose of the Study:

• To investigate the chromatin accessibility landscape within breast cancer tumors.
• To explore the molecular mechanisms underlying intratumoral heterogeneity.
• To identify how epigenetic regulation contributes to divergent tumor microenvironments and diversity.

Main Methods:

• Utilized spatial ATAC-seq to profile chromatin accessibility in tumors from six BC patients.
• Analyzed regulatory modules, immune cell composition, and stromal structures.
• Investigated epigenetic regulation in tumor subclones with distinct immune infiltration.

Main Results:

• Revealed significant heterogeneity in tumor regulatory modules.
• Identified spatial variations in immune cell composition and stromal architecture.
• Discovered two tumor subclones with distinct immune infiltration patterns due to regulatory cascades.
• Highlighted the role of epigenetic regulation in shaping tumor microenvironments and phenotypic diversity.

Conclusions:

• Spatial ATAC-seq provides a framework for studying the molecular architecture of ITH.
• Epigenetic regulation contributes to the divergent tumor microenvironments and phenotypic diversity of BC subclones.
• The study offers novel insights into BC ITH mechanisms, suggesting potential therapeutic intervention strategies.