Abstract 5319: Simultaneous spatial epigenomic and transcriptomic analysis of human breast cancer reveals regulatory patterns governing tumor and microenvironment architecture at the cellular level

Recent advances in spatial transcriptomics and spatial proteomics have enabled increasingly complex questions on the nature of gene regulation and expression in cellular subtypes in tumor tissue and the tumor microenvironment. However, most spatial omics techniques do not profile the epigenomic landscape responsible for downstream gene expression. Furthermore, current spatial technologies have yet to profile the epigenome and transcriptome simultaneously, and thus it remains a challenge to correlate multi-omics data across sections of extremely heterogenous tumor tissue. Co-profiling of spatial epigenomics and transcriptomics using principles of Deterministic Barcoding in Tissue for spatial omics sequencing (DBiT-seq) has been demonstrated on normal brain tissue. Joint spatial profiling of chromatin states and whole transcriptome in tissue allows for parallel characterization of gene regulation programs across all cell types, while preserving the tissue architecture for greater understanding of the cellular environment. Here we present the first application of spatial ATAC-seq and spatial transcriptomics on the same tissue section to characterize the tumor microenvironment of an infiltrating ductal carcinoma, the most common type of breast cancer, and adjacent normal tissue. Distinct spatial clusters representing different cell subtypes were identified via both spatial chromatin accessibility and spatial transcriptomics. Spatial ATAC-seq profiling of accessible regulatory elements correlated well with RNA expression. Spatial patterns of transcription factor motif accessibility also correlated well with the observed transcriptional program of tumor tissue. When compared to adjacent normal tissue, spatial co-profiling of chromatin accessibility and the transcriptome revealed that the epigenetic landscape is significantly altered in the tumor. Future work will focus on development of co-profiling of histone modifications and the transcriptome to enable the study of another layer of the epigenomic landscape, especially as targeting epigenetic modifiers such as HDACis in breast cancer is being tested in clinical trials with other standard of care therapeutics. Overall, we present a solution to profile multiple layers of gene regulation and expression with spatial context, which can be applied to most tumor types for better understanding of tumorigenesis and the consequences of new targeted therapies. Citation Format: Katelyn Noronha, Molly Wetzel, Gumaro Rojas, Jennifer Garbarino, James McGann, Jose Perez, Machele Riccio, Danijela Pavic, Jaden Joaquin, Joshua Barnett, Jeffrey Sabina, Colin Ng. Simultaneous spatial epigenomic and transcriptomic analysis of human breast cancer reveals regulatory patterns governing tumor and microenvironment architecture at the cellular level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5319.