Targeting lipid metabolism in pancreatic cancer [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1074765 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27921468_1.fastq.gz | Fastqsanger.gz | |||
| SRR27921468_2.fastq.gz | Fastqsanger.gz | |||
| SRR27921469_1.fastq.gz | Fastqsanger.gz | |||
| SRR27921469_2.fastq.gz | Fastqsanger.gz | |||
| SRR27921470_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
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Project description:Targeting lipid metabolism in pancreatic cancer
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Project description:Targeting lipid metabolism in pancreatic cancer [CRISPR]
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Project description:Pancreatic ductal adenocarcinoma (PDAC) thrives in a nutrient-deprived microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in pre-clinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning as a novel and targetable vulnerability in PDAC. Through comprehensive metabolic analyses we find that PIKfyve inhibition obligates PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggers a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, including genes such as FASN and ACACA. These results suggest that targeting PIKfyve disrupts lysosome-dependent lipid metabolism in PDAC and may be a favorable metabolic target for therapeutic development. Further, this data suggests that one could take advantage of this synthetic dependency by co-targeting PIKfyve and FASN or ACACA as a therapeutic strategy.
2024-04-10 | GSE255375 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) thrives in a nutrient-deprived microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in pre-clinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning as a novel and targetable vulnerability in PDAC. Through comprehensive metabolic analyses we find that PIKfyve inhibition obligates PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggers a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, including genes such as FASN and ACACA. These results suggest that targeting PIKfyve disrupts lysosome-dependent lipid metabolism in PDAC and may be a favorable metabolic target for therapeutic development. Further, this data suggests that one could take advantage of this synthetic dependency by co-targeting PIKfyve and FASN or ACACA as a therapeutic strategy.
2024-04-10 | GSE255377 | GEO
Project description:Lipid metabolism reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy
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Project description:Pancreatic ductal adenocarcinoma (PDAC) treatment is challenging. Determining the metabolic pathways that regulate lipids will provide new insights into PDAC therapeutic strategies. Sterol regulatory element binding transcription factor 1 (SREBP-1) regulates multiple cancer pathways; however, its role in the tumor immune microenvironment and cancer immunotherapy is unknown. Herein, we integrated our large PDAC cohort data and identified that SREBP-1, as a master transcriptional regulator of lipogenesis, aggravated lipid metabolism reprogramming in PDAC. Furthermore, interrupting lipid metabolism by targeting SREBP-1 suppressed PDAC cell growth and enhanced antitumor immunity in vitro and in vivo. We demonstrated that SREBP-1 binds to the PD-L1 (programmed cell death 1 ligand 1) promoter to suppress its transcription. Importantly, SREBP-1 binds to the PCSK9 (proprotein convertase subtilisin/kexin type 9) promoter, which regulated PD-L1 levels via lysosome-mediated degradation and aggravated tumor microenvironment immunosuppression. Targeting the SREBP-1- PCSK9 axis using available drugs sustained the remission of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine. In summary, targeting lipid metabolism suppressed tumor growth and relieved tumor immunosuppression in PDAC.
2025-02-28 | GSE290259 | GEO
Project description:Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer
| PRJNA1164286 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered that PIKFYVE is overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis and specifically sphingolipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.
2025-02-19 | GSE277831 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered that PIKFYVE is overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis and specifically sphingolipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.
2025-02-19 | GSE277830 | GEO
Project description:Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer [ChIP-seq]
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