Philip M. Spanheimer

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Breast cancer metastasis remains the leading cause of disease-related mortality, yet the regulatory mechanisms enabling tumor cells to adapt to distant tissue environments remain poorly defined. In this study, we generated a multiomic resource integrating transcriptomic (RNA sequencing) and chromatin accessibility [Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq)] profiles from estrogen receptor–positive primary breast tumors and matched liver and lung metastases obtained from the same patients, including diagnostic and postmortem specimens. This design enabled direct intrapatient comparisons of primary and metastatic regulatory landscapes. We identified extensive reprogramming of chromatin accessibility and gene expression in metastatic lesions relative to primary tumors, indicating widespread regulatory remodeling. Peak-to-gene correlation analysis uncovered thousands of metastasis-associated enhancer–gene linkages, with metastatic samples exhibiting significantly increased enhancer connectivity. These rewired enhancer networks preferentially targeted clinically relevant genes, including receptor interacting serine/threonine kinase 4, inositol-3-phosphate synthase 1, and Ras-related protein Rab-3D, which were associated with three or more enhancers in metastases but not in primary tumors. Furthermore, ATAC-seq footprinting combined with gene expression analysis revealed distinct, tissue-specific transcription factor (TF) activity profiles in liver and lung metastases, including ESR1, that were not explained by TF expression levels alone. Together, these data provide a resource of metastasis-specific regulatory elements and their cognate TFs, revealing new regulatory vulnerabilities that may be therapeutically exploitable. Implications:These findings support a model in which breast cancer metastasis is driven by enhancer regulatory reprogramming, allowing tumor cells to adapt to a variety of microenvironments.

Supplementary Data File 2 from Integrative Transcriptional and Chromatin Analyses Reveal Enhancer-Mediated Regulatory Programs Driving Breast Cancer Metastasis

Supplementary Data File 4 from Integrative Transcriptional and Chromatin Analyses Reveal Enhancer-Mediated Regulatory Programs Driving Breast Cancer Metastasis

Supplementary Data File 3 from Integrative Transcriptional and Chromatin Analyses Reveal Enhancer-Mediated Regulatory Programs Driving Breast Cancer Metastasis

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Supplementary Data File 6 from Integrative Transcriptional and Chromatin Analyses Reveal Enhancer-Mediated Regulatory Programs Driving Breast Cancer Metastasis

Supplementary Data File 7 from Integrative Transcriptional and Chromatin Analyses Reveal Enhancer-Mediated Regulatory Programs Driving Breast Cancer Metastasis

Supplementary Data File 8 from Integrative Transcriptional and Chromatin Analyses Reveal Enhancer-Mediated Regulatory Programs Driving Breast Cancer Metastasis

Figure S2. Transcription factor footprinting and TFAS activity across metastatic tissues.