Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis
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ABSTRACT:
PROVIDER: PRJNA971725 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24518340.fastq.gz | Fastqsanger.gz | |||
| SRR24518341.fastq.gz | Fastqsanger.gz | |||
| SRR24518342.fastq.gz | Fastqsanger.gz | |||
| SRR24518343.fastq.gz | Fastqsanger.gz | |||
| SRR24518344.fastq.gz | Fastqsanger.gz |
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Project description:Dysregulation of the mitogen-activated protein kinase interacting kinases 1/2 (MNK1/2)-eukaryotic initiation factor 4E (eIF4E) signaling axis promotes breast cancer progression. MNK1 is known to influence cancer stem cells (CSCs); self-renewing populations that support metastasis, recurrence, and chemotherapeutic resistance, making them a clinically relevant target. The precise function of MNK1 in regulating CSCs, however, remains unexplored. Here, we generated MNK1 knockout cancer cell lines, resulting in diminished CSC properties in vitro and slowed tumor growth in vivo. Using a multiomics approach, we functionally demonstrated that loss of MNK1 restricts tumor cell metabolic adaptation by reducing glycolysis and increasing dependence on oxidative phosphorylation. Furthermore, MNK1-null breast and pancreatic tumor cells demonstrated suppressed metastasis to the liver, but not the lung. Analysis of The Cancer Genome Atlas (TCGA) data from breast cancer patients validated the positive correlation between MNK1 and glycolytic enzyme protein expression. This study defines metabolic perturbations as a previously unknown consequence of targeting MNK1/2, which may be therapeutically exploited.
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Project description:The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation
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Project description:This SuperSeries is composed of the SubSeries listed below. Abstract To selectively express cell type–specific transcripts during development, it is critical to maintain genes required for other lineages in a silent state. Here, we show in the Drosophila male germline stem cell lineage that a spermatocyte-specific zinc finger protein, Kumgang (Kmg), working with the chromatin remodeler dMi-2 prevents transcription of genes normally expressed only in somatic lineages. By blocking transcription from normally cryptic promoters, Kmg restricts activation by Aly, a component of the testis-meiotic arrest complex, to transcripts for male germ cell differentiation. Our results suggest that as new regions of the genome become open for transcription during terminal differentiation, blocking the action of a promiscuous activator on cryptic promoters is a critical mechanism for specifying precise gene activation.
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Project description:Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the precursor lesions of Pdx1+;K-rasG12D/+;Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes P-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that, while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Murine mutants with pancreatic specific loss of Pten (Pten +/-) and K-ras activation (K-rasG12D) and either COX-2 over-expression (Cox-2 COE) or knockout (Cox-2 KO) under regulation of the Pdx-1 promoter developed pancreatic ductal adenocarcinoma. RNA was extracted from pancreatic tumors from individual mutants with pathology thought to closely mimic the human disease. Pancreatic tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.
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