Rearrangement of 3D genome organization in breast cancer epithelial - mesenchymal transition and metastasis organotropism

Abstract Breast cancer cells exhibit organotropism during metastasis, showing preferential homing to certain organs such as bone, lung, liver, and brain. One potential explanation for this organotropic behavior is that cancer cells gain properties that enable thriving in certain microenvironments. Such specific metastatic traits may arise from gene regulation at the primary tumor site. Spatial genome organization plays a crucial role in oncogenic transformation and progression, but the extent to which chromosome architecture contributes to organ-specific metastatic traits is unclear. This work characterizes chromosome architecture changes associated with organotropic metastatic traits. By comparing a collection of genomic data from different subtypes of localized and lung metastatic breast cancer cells with both normal and cancerous lung cells, we find important trends of genomic reorganization. The most striking differences in 3D genome compartments segregate cell types according to their epithelial vs. mesenchymal status. This EMT compartment signature occurs at genomic regions distinct from transcription-defined EMT signatures, suggesting a separate layer of regulation. Specifically querying organotropism, we find 3D genome changes consistent with adaptations needed to survive in a new microenvironment, with lung metastatic breast cells exhibiting compartment switch signatures that shift the genome architecture to a lung cell-like conformation and brain metastatic prostate cancer cells showing compartment shifts toward a brain-like state. TCGA patient data reveals gene expression changes concordant with these organ-permissive compartment changes. These results suggest that genome architecture provides an additional level of cell fate specification informing organotropism and enabling survival at the metastatic site.