Spatial Chromatin Accessibility Analysis of Intratumor Heterogeneity in Breast Cancer

Intratumoral heterogeneity (ITH) is a major driver of mortality in breast cancer (BC) patients and a critical factor in the variable therapeutic outcomes observed in BC treatment. Understanding the mechanisms underlying ITH is essential for advancing both clinical and basic BC research. Chromatin accessibility is critical for regulation of gene expression and cellular identity and plays a central role in shaping ITH and tumor evolution. However, studying chromatin accessibility in situ has been challenging due to the availability of technical platforms. Here, we leveraged the spatial ATAC-seq platform to profile the chromatin accessibility landscape of tumors from six BC patients. Our analyses revealed prominent heterogeneity within tumor regulatory modules and spatial variations in immune cell composition and stromal structures, offering a framework for investigation of the molecular architecture underlying ITH. Moreover, we identified two tumor subclones with potential common origin but distinct immune infiltration conferred by regulatory cascades, suggesting that epigenetic regulation may further contribute to the divergent tumor microenvironments and phenotypic diversity of these subclones. Our study provides novel insights into the molecular mechanisms driving ITH and opens up potential avenues for therapeutic intervention.