Polyploid cisplatin-resistant cancer cells have altered nuclear organization and epigenomic status

Chemotherapy resistance remains a critical barrier in cancer treatment, partly driven by polyploid cells that survive therapy and contribute to tumor recurrence. Here, we investigated epigenomic and transcriptional changes associated with cisplatin-surviving polyploid cells compared to parental cancer cells in prostate cancer (PC3) and triple-negative breast cancer (MDA-MB-231) cell lines. We observed persistent dysregulation of chromatin compaction and altered nuclear structure in polyploid cells following cisplatin treatment. Genome-wide chromatin accessibility profiling via ATAC-seq revealed significant remodeling, notably decreased promoter accessibility at proliferation-associated loci and increased accessibility of distal regulatory elements linked to inflammation and stress response. RNA-seq analyses demonstrated a coordinated transcriptional shift away from proliferative signatures toward inflammatory and survival pathways, including activation of NF?B, interferon response, and integrated stress response pathways. Importantly, we identified subsets of genes showing concordant changes in promoter accessibility and transcriptional activity, directly linking chromatin remodeling to transcriptional reprogramming. These integrated findings highlight the role of chromatin dynamics and epigenetic plasticity in chemotherapy resistance, demonstrating that widespread chromatin accessibility changes facilitate the transition to a stress-adapted, polyploid cell state. This study provides new insights into the molecular mechanisms supporting cancer cell persistence after chemotherapy. Overall design: PC3 (prostate cancer cell line) were treated with cisplatin and surviving cells were analyzed 1, 5 and 10 days following chemotherapy (DPT). PC3 cells were treated with docetaxel and surviving cells were analyzed 1, 5, 10 days following chemotherapy. SIngle cell RNA sequencing was performed on untreated cell lines and surviving cells 1, 5, and 10 DPT in biological triplicate. Parse Biosciences sequencing is done by combinatorial barcoding, whereby cells from every sample type is present in each sublibrary. Sublibraries are sequenced and individual cells called by barcode identifier.