Ying, H. Q., Kimmelman, A. C., Lyssiotis, C. A., Hua, S. J., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H. L., Coloff, J. L., Yan, H. Y., Wang, W., Chen, S. J., Viale, A., Zheng, H. W., Paik, J. H., Lim, C., Guimaraes, A. R., Martin, E. S., Chang, J., Hezel, A. F., Perry, S. R., Hu, J., Gan, B. Y., Xiao, Y. H., Asara, J. M., Weissleder, R., Wang, Y. A., Chin, L., Cantley, L. C., DePinho, R. A. (April 2012) Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism. Cell, 149 (3). pp. 656-670. ISSN 0092-8674
Abstract
Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-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 PDAC.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | N-LINKED CARBOHYDRATE K-RAS ADDICTION DUCTAL ADENOCARCINOMA SUPPRESSOR GENES CELL-GROWTH CANCER INDUCTION MYC EXPRESSION BIOLOGY Biochemistry & Molecular Biology Cell Biology |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Zheng lab CSHL Cancer Center Program > Signal Transduction |
| Depositing User: | Matt Covey |
| Date: | April 2012 |
| Date Deposited: | 22 Aug 2014 19:52 |
| Last Modified: | 16 Oct 2015 15:39 |
| PMCID: | PMC3472002 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30697 |
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