Cell Cycle Reprogramming Mediates Acquired Oxaliplatin Resistance in Pancreatic Cancer [cell lines]
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ABSTRACT:
PROVIDER: PRJNA1280177 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited treatment options. While oxaliplatin-based (Oxa) therapy, such as FOLFIRINOX, has improved outcomes in select patients, Oxa resistance significantly limits its efficacy. This study investigates cell cycle mechanisms driving Oxa resistance and explores targeting these pathways as a therapeutic strategy. Experimental Design: Murine KPC and human Panc1 oxaliplatin-resistant (Oxa-R) cell lines were established. RNA sequencing, Western blotting, and flow cytometry were used to analyze DNA damage and cell cycle regulators. Viability assays and a murine orthotopic PDAC model were employed to evaluate the therapeutic potential of CDK4/6 inhibition with Oxa. Results: Oxa-R cell lines exhibited slower proliferation rates, reduced response to Oxa treatment, and significant upregulation of G2/M and E2F1 signaling pathways, findings that correlated with poor survival outcomes in human clinical datasets. In Oxa-sensitive PDAC cells, Oxa treatment activated the ATR-Chk1 pathway, leading to cyclin D1 suppression and apoptosis. In contrast, Oxa resistance was characterized by compensatory upregulation of CDK4/6 signaling, which enabled cells to bypass DNA damage-induced cell cycle arrest. Notably, the addition of CDK4/6 inhibitors restored Oxa sensitivity in resistant cell lines, resulting in enhanced apoptosis in vitro and significantly reduced tumor growth in vivo. Conclusion: Oxa resistance in PDAC is mediated by cell cycle dysregulation involving cyclin D1 and CDK4/6. Targeting CDK4/6 with Abemaciclib reverses resistance and enhances Oxa efficacy, offering a promising therapeutic strategy for resistant PDAC.
2025-06-30 | GSE300379 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE22477: PHF8 mediates histone demethylation events in cell cycle progression [expression] GSE22478: PHF8 mediates histone demethylation events in cell cycle progression [ChIP-Seq] Refer to individual Series
2010-08-31 | E-GEOD-22400 | biostudies-arrayexpress
Project description:Resistance to oxaliplatin (OXA) is a complex process affecting the outcomes of metastatic colorectal cancer (CRC) patients treated with this drug. The NF-kBsignalling pathway deregulation has been proposed as an important mechanism involved in this phenomenon. Here, we show that NF-kBwas hyperactivated in in vitro models of OXA-acquired resistance but was attenuated by the addition of Curcumin, a non-toxic NF-kB inhibitor. The concomitant combination of Curcumin+OXA was more effective and synergistic in cell lines with acquired resistance to OXA, leading to the reversion oftheir resistant phenotype, through the inhibition of the NF-kBsignalling cascade. Transcriptomic profiling revealed the up-regulation of three NF-KB-regulated CXC-chemokines, CXCL8, CXCL1 and CXCL2, in the resistant cells thatwere more efficiently down-regulated after OXA+Curcumin treatment as compared to the sensitive cells. Moreover, CXCL8 and CXCL1 gene silencing made resistant cells more sensitive to OXA through the inhibition of the Akt/NF-kBpathway. High expression of CXCL1 in FFPE samples from explant cultures of CRC patients-derived liver metastaseswas associated with response to OXA+Curcumin.In conclusion, we suggest that combination of OXA+Curcumincould be an effective treatment in CRC patients after progression to OXA-based chemotherapy being CXCL1a good candidate predictive marker to this treatment.
2016-12-07 | GSE76092 | GEO
Project description:We sought to examine changes in gene expression of PANC1 cells with acquired resistance to oxaliplatin chemotherapy. Cultures of PANC1 cells, an established pancreatic cancer cell line, were exposed to oxaliplatin chemotherapy over multiple passages and acquired a stable drug-resistant phenotype labeled as PANC1OR. Previously reported immunofluorescence and western blots indicate that PANC1OR exhibit increased EMT (increased cytoskeletal vimentin, decreased E-cadherin and fibroblast-like morphology). Here we sought to examine more broadly the differential expression of genes associated with acquired drug resistance in these cells.
2024-12-19 | GSE279527 | GEO
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-beta 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.
2025-07-23 | GSE299427 | GEO
Project description:To explore the circadian functions of the miRNAs derived from these circadian primary miRNA transcripts, we focused on miR-378 and examined the transcriptome changes in mouse livers upon miR-378 over-expression at two circadian time points, CT10 and CT22. First, we observed a significant over-representation of the circadian oscillating genes affected by miR-378 over-expression. Cell cycle genes are further enriched in the affected circadian oscillating genes, which implied that miR-378 mediates the circadian control of cell cycle. Our examination of circadian regulatory network involving miR-378 suggests that miR-378 mediates the circadian control of cell cycle and metabolism by forming either coherent or incoherent feed-forward loops with circadian TFs.
2016-09-21 | GSE73308 | GEO
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.
2025-07-15 | GSE298524 | GEO
Project description:Dysfunction of cell cycle genes can lead to mitosis disruption and chromosomal instability (CIN), which is blamed for poor prognosis in colorectal cancer (CRC) patients, no matter with chemotherapy or not. Discovery therapeutic targets to abnormal cell cycle pathways in CRC may help to improve current therapy. By genome-widely profiling of differential expressed genes in 54 pairs of human colorectal tumor with matched normal mucosa, we found a functional enrichment in PLK1 signaling. Tumors with enriched PLK1 signaling are accompanied with dysfunction pathways related to cell cycle. Total PLK1 and phosphorylated PLK1 protein expression are associated with tumor recurrence and poor overall survival in a cohort of CRC patients. Combining PLK1 inhibitor with oxaliplatin shows a synergize effect to suppress the growth of CRC cell lines, xenograft tumors, preclinical patient-derived organoid and patient-derived xenograft tumors. RNA-seq data reveals that the cell cycle pathways were activated in oxaliplatin group but inhibited after PLK1 inhibitor treatment. CDC7 may be a key downstream effector of PLK1 induced oxaliplatin resistance and can be druggable. Further investigation showed that PLK1 inhibitor suppress the CDC7 expression via c-MYC transcriptional control. A strong positive correlation between PLK1 and CDC7 has been further confirmed in patients. Strikingly, functional studies confirm that combining CDC7 inhibitor with oxaliplatin can recapitulate the synergize effect in various CRC models, highlighting pharmacological target PLK1-MYC-CDC7 signaling as a potential therapeutic strategy for oxaliplatin based chemotherapy.
2023-10-24 | GSE160089 | GEO
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.
2025-07-23 | GSE299428 | GEO
Project description:To identify key drivers of oxaliplatin resistance, we collected and analyzed the DEGs between oxaliplatin-resistant and oxaliplatin-non-resistant patient samples
2023-02-28 | GSE206501 | GEO