Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance [Hi-C]

Organoids or spheroids have emerged as a physiologically relevant in vitro preclinical model to study patient-specific diseases. A recent study used spheroids of MCF10 cells to model breast cancer progression and identified targetable alterations more similar to those in vivo. Thus, it is practical and essential to explore and characterize the spheroids of the commonly used human breast cancer (BC) cells. This study conducted Hi-C analyses in three-dimensional (3D) spheroids of MCF10A, MCF7 and MCF7TR cells and compared TADs and looping genes with those in 2D monolayers. We found that chromatin domains and looping genes' strength have drastically changed during the 3D culture growth, although we identified very similar numbers of TADs and looping genes. We further identified novel 3D growth-specific looping genes within Hippo relevant pathways, of which two genes showed potential prognostic values in measuring the outcome of the endocrine treatment. We finally confirmed a few selected Hippo relevant pathways genes with enhanced looping in breast cancer patient tissues' organoid. Hence, our work has provided significant insights into our understanding of 3D-growth-specific chromatin architecture in tamoxifen-resistant breast cancer. Overall design: Hi-C experiment of 3 cell types in 3D spheroids, 2 biological replicates for each cell type.