ATAC-seq of oxaliplatin resistant HCT116

Drug resistance and distant metastases are leading causes of mortality in colorectal cancer (CRC), yet the molecular mechanisms linking these processes remain elusive. In this study, we demonstrate that acquired resistance to oxaliplatin, a first-line chemotherapeutic in CRC, enhances metastatic potential through transcriptional reprogramming. Using a clinically relevant dosing regimen, we generated oxaliplatin-resistant CRC cells that displayed increased metastatic potential. Integrated transcriptomic and phenotypic analyses revealed that dysregulated cholesterol biogenesis amplifies TGF-b signaling, which in turn drives expression of SERPINE1, that serves as a key effector of both oxaliplatin resistance and metastasis. Furthermore, we uncovered a SERPINE1-associated nine-gene expression signature, RESIST-M, that robustly predicts overall and relapse-free survival across distinct patient cohorts. Notably, RESIST-M stratifies a high-risk subtype of CMS4/iCMS3-fibrotic patients that display the poorest prognosis, underscoring its clinical relevance. Targeting of SERPINE1 or cholesterol biosynthesis re-sensitized resistant, pro-metastatic cells to oxaliplatin in mouse xenograft models. Altogether, this study uncovers a mechanistic link between metabolic rewiring and transcriptional plasticity underlying therapy-induced metastasis in primary CRC. Additionally, it also reveals actionable vulnerabilities that offer both prognostic value and therapeutic potential. Overall design: HCT116 cells were treated with 0.5 uM (low dose; LD), 5 uM (mid dose; MD) or 80 uM (high dose; HD) for 72 hours before changing to drug free media. Cells were then subcultured and treated again with the same dose for 72 hours. Cells were treated for 10 cycles. Cells were subsequently cultured in drug free media and used for ATAC-seq.