Peritoneal Metastases from Colorectal Cancer belong to Consensus Molecular Subtype 4 and are sensitized to oxaliplatin by inhibiting reducing capacity
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ABSTRACT:
PROVIDER: PRJNA787646 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17189200.fastq.gz | Fastqsanger.gz | |||
| SRR17189300.fastq.gz | Fastqsanger.gz | |||
| SRR17189400.fastq.gz | Fastqsanger.gz | |||
| SRR17189500.fastq.gz | Fastqsanger.gz | |||
| SRR17189600.fastq.gz | Fastqsanger.gz |
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Project description:Background: Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance. Experimental design: We generated a biobank consisting of 35 primary tumor regions and 59 paired PM from 12 patients. All samples were analyzed by RNA sequencing. We also generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin Results: PM displayed various hallmarks of aggressive CRC biology. The vast majority of PM and paired primary tumors belonged to the Consensus Molecular Subtype 4 (CMS4). PMDO cultures were resistant to oxaliplatin and expressed high levels of glutamate-cysteine ligase (GCLC) causing detoxification of oxaliplatin through glutathione synthesis. Genetic or pharmacological targeting of GCLC sensitized PMDOs to a 1-hour exposure to oxaliplatin, through increased platinum-DNA adduct formation Conclusions: These results link oxaliplatin resistance of colorectal PM to their CMS4 status and high reducing capacity. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin
2022-06-15 | GSE190609 | GEO
Project description:BackgroundPeritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance.Experimental designWe generated a biobank consisting of 35 primary tumour regions and 59 paired PM from 12 patients. All samples were analysed by RNA sequencing. We also generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin.ResultsPM displayed various hallmarks of aggressive CRC biology. The vast majority of PM and paired primary tumours belonged to the Consensus Molecular Subtype 4 (CMS4). PMDO cultures were resistant to oxaliplatin and expressed high levels of glutamate-cysteine ligase (GCLC) causing detoxification of oxaliplatin through glutathione synthesis. Genetic or pharmacological targeting of GCLC sensitised PMDOs to a 1-h exposure to oxaliplatin, through increased platinum-DNA adduct formation.ConclusionsThese results link oxaliplatin resistance of colorectal PM to their CMS4 status and high reducing capacity. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin.
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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.
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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.
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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.
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