Project description:Gene expression between DLD1 and DLD1 derived oxaliplatin resistant clones (DLD/OHP1, DLD/OHP4, and DLD/OHP5) was assessed Gene expression between HCT116 and HCT116 derived oxaliplatin resistant clones (HCT/OHP1, HCT/OHP3, and HCT/OHP5) was assessed
Project description:Oxaliplatin resistance frequently leads to therapeutic failure in colorectal cancer (CRC). Increasing evidence has shown that noncoding RNAs (ncRNAs) play pivotal roles in chemoresistance of CRC. However, the roles and mechanisms of ncRNAs in oxaliplatin resistance are not well understood. In this study, to identify the ncRNAs induced by oxaliplatin, we profile the expression of ncRNAs in oxaliplatin-resistant HCT116 CRC cells (HCT116oxR) and parental HCT116 cells using next-generation sequencing technology.
Project description: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.
Project description:To explore the mechanisms associated with oxaliplatin resistance, we compared gene expression in xenograft tumors derived from human colorectal cancer tumor cells HCT116 and its oxaliplatin resistant clones (HCT/OHP1 and HCT/OHP5).
Project description:HCT116 parental, HCT116 5-FU resistant and HCT116 oxaliplatin resistant cells have been transiently treated with with their respective drug (5-FU or oxaliplatin) for 0, 6 12 or 24h in 3 independent experiments.
Project description:To identify key drivers of oxaliplatin resistance, we collected and analyzed the DEGs between oxaliplatin-resistant and oxaliplatin-non-resistant patient samples
Project description:Mapping the global chromatin connectivity network in colorectal cancer cell HCT116 and Oxaliplatin-resistant cell HCT116OxR [ATAC-seq]
Project description:Numerous studies have highlighted the critical role of genetic and epigenetic modifications in the regulation of oxaliplatin resistance, but whether changes involving chromatin structure have not been fully investigated. We have integrated a variety of techniques to explore a comprehensive overview of chromatin changes in oxaliplatin-resistant processes.
Project description:Aim: mRNA profile of HCT116 human colon cancer cells to study the early response of cells to oxaliplatin exposure at low doses (0.5µM) Results: After treatment with oxaliplatin for 24h at 0.5µM, only a very small fraction of genes were mis-regulated. They fall mainly include P53-response genes, genes regulating inflammation, or genes regulating cytoskeleton.