GSE201434
Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [RNA-Seq]
Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. However, little is known about the rewiring of the 3D chromatin landscape during cancer progression to a chemotherapy-resistant state. We utilized a patient-derived xenograft (PDX) mouse model of triple-negative breast cancer (UCD52) to characterize changes in the 3D structure between the primary tumor and carboplatin-resistant state. Systematic integration of matched chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing data revealed a widespread increase in short-range (<2Mb) interactions with the corresponding increase in chromatin looping and topologically associating domain (TAD) formation, chromatin state switching into a more active state, large-scale deletions, amplification of ATP-binding cassette (ABC) transporters and nearly complete shutdown of drug metabolism pathways. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of many aggressiveness-, metastasis- and other cancer-related pathways. Transcriptome changes suggest the role of downregulated protein-coding genes and upregulated long-noncoding RNAs in drug resistance. Integrative analysis confirmed increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial metabolic processes. Our results highlight that 3D genome remodeling may be a key mechanism underlying drug resistance. Overall design: RNA-sequencing analysis performed on three replicates for each of the two phenotypes (primary tumor and carboplatin-resistant state).