Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA147317 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Kras is required for pancreatic tumor maintenance through regulation of hexosamine biosynthesis and the non-oxidative pentose phosphate pathway
2020-04-03 | E-GEOD-32277 | ExpressionAtlas
Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC. Primary pancreatic tumor lines were established from p48Cre tetO_LKrasG12D ROSA_rtTAL+ p53L+ mice. Five independent tumor lines (iKras1-5) were used for pancreatic injection into nude mice to generate orthotopic tumors. The mice were kept on doxycycline for 2 weeks until obvious tumor formation. Half of the animals were pulled off doxycycline for 24 hours. Tumors with over 75% cellularity were collected for total RNA prepartion. For in vitro expression profiles, the same five tumor lines were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared. For control samples, two independent tumor lines from LSL-KrasG12D p53L+ tumors were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared.
2012-04-29 | E-GEOD-32277 | biostudies-arrayexpress
Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC.
2012-04-30 | GSE32277 | GEO
Project description:Cancer cells heavily rely on nicotinamide adenine dinucleotide phosphate (NADPH) to counteract oxidative stress and facilitate reductive biosynthesis. One crucial route for NADPH production operates through the oxidative pentose phosphate pathway, with a pivotal step at glucose-6-phosphate dehydrogenase (G6PD). This study delves into the repercussions of G6PD ablation on the development of lung tumors driven by the KRAS oncogene and deficient in LKB1 (KL). The research involved comparing the growth of KL lung tumors with or without G6PD, revealing a significant inhibition of KL lung tumor growth upon G6PD loss. Subsequently, RNA-seq analysis was employed to identify the alterations in gene expression following G6PD deletion, providing insights into the underlying mechanisms.
2024-01-23 | GSE253613 | GEO
Project description:Stomatin-like protein 2 (SLP-2) is associated with poor prognosis in several types of cancer, including pancreatic cancer; however, the molecular mechanism of its involvement remains elusive. This study aimed to elucidate the role of this protein in the development of pancreatic cancer. Human pancreatic cancer cell lines AsPC-1 and PANC-1 were transfected by a vector expressing SLP-2 shRNA. Analyses of cell proliferation, migration, invasion, chemosensitivity, and glucose uptake were performed, while a mouse xenograft model was used to evaluate the functional role of SLP-2 in pancreatic cancer. Immunohistochemical analysis was retrospectively performed on human tissue samples to compare expression between the primary site (n=279) and the liver metastatic site (n=22). Furthermore, microarray analysis was conducted to identify genes correlated with SLP-2. In vitro analysis demonstrated that cells in which SLP-2 was suppressed showed reduced cell motility and glucose uptake, while in vivo analysis showed a dramatic decrease in the number of liver metastases. Immunohistochemistry revealed that SLP-2 was elevated in liver metastatic sites. Microarray analysis indicated this protein regulated the expression of glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway. SLP-2 contributes to the malignant character of pancreatic cancer by inducing liver metastasis. Cell motility and glucose uptake may be induced via the hexosamine biosynthesis pathway, through the expression of GFPT2. This reveals a new mechanism of liver metastasis and implies that SLP-2 and its downstream pathway could provide novel therapeutic targets for pancreatic cancer.
2020-12-11 | GSE162981 | GEO
Project description:The initiation of heartbeat is an essential step in cardiogenesis in the heart primordium, but it remains unclear how intracellular metabolism responds to increased energy demands after heartbeat initiation. In this study, embryos in Wistar rats at embryonic day 10, at which heartbeat begins in rats, were divided into two groups by the heart primordium before and after heartbeat initiation and their metabolic characteristics were assessed. Metabolome analysis revealed that increased levels of ATP, a main product of glucose catabolism, and reduced glutathione, a by-product of the pentose phosphate pathway, were the major determinants in the heart primordium after heartbeat initiation. Glycolytic capacity and ATP synthesis-linked mitochondrial respiration were significantly increased, but subunits in complexes of mitochondrial oxidative phosphorylation were not upregulated in the heart primordium after heartbeat initiation. Hypoxia-inducible factor (HIF)-1α was activated and a glucose transporter and rate-limiting enzymes of the glycolytic and pentose phosphate pathways, which are HIF-1α-downstream targets, were upregulated in the heart primordium after heartbeat initiation. These results suggest that the HIF-1α-mediated enhancement of glycolysis with activation of the pentose phosphate pathway, potentially leading to antioxidant defense and nucleotide biosynthesis, covers the increased energy demand in the beating and developing heart primordium.
2021-10-14 | GSE185702 | GEO
Project description:Control of regulatory T cell function by the non-oxidative pentose phosphate pathway
| PRJNA721880 | ENA
Project description:Depletion of Nrf2 leads to an increase in cellular ROS, reduced glutathione and thiols, and profound reprogramming of metabolism. Unbiased transcriptome analyses show that key enzymes of glycolysis, pentose phosphate pathway, and glutathione cycle are significantly downregulated, while enzymes of arginine and medium-chain fatty acids metabolism are upregulated. Besides glutamine, pancreatic cancer cells deficient of Nrf2 axis become highly dependent on arginine, which is channelled into the synthesis of phosphocreatine and polyamines. Key enzymes of the creatine pathway, gatm and ckb, are more expressed and more active in Nrf2(-/-) than in WT cells. This metabolism shift creates an energy buffer that enables pancreatic cancer cells to handle increased energy demand. Metabolomic analysis showed that 12% of the creatine pool is phosphorylated in Nrf2(-/-) cells, while the level drops to < 0.1% in WT cells. The inhibition of the creatine pathway with cyclocreatine in Nrf2(-/-) cells, reduces by 43% the ATP level and by 70% invasion rate in matrigel. Furthermore, we found that combination therapies that can target simultaneously the creatine pathway and the KRAS G12D-Nrf2 axis produce a stronger anticancer effect than monotherapies. Taken together, our data provide the basis for the rationale design of new combination therapies against pancreatic cancer. The KRAS G12D-Nrf2 axis controls redox homeostasis and metabolism in PDAC cells. Suppression of KRAS G12D-Nrf2 decreases glycolysis, PPP and glutathione cycle and promotes a metabolic shift of arginine into the synthesis of phosphocreatine
2023-12-12 | GSE217965 | GEO
Project description:Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions. However, how metabolism influences fate determination remains unclear. Here, we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, new organelles are immature and metabolically less active. Upon cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with old mitochondria imposing oxidative energy metabolism inducing differentiation. High pentose phosphate pathway flux, promoting redox maintenance, is favoured in cells receiving newly synthesised mitochondria, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria.
2021-12-20 | PXD010667 | Pride
Project description:The pentose phosphate pathway regulates the circadian clock
| PRJNA300419 | ENA