Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

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

URL: http://www.ncbi.nlm.nih.gov/pubmed/22541435
DOI: 10.1016/j.cell.2012.01.058

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: http://repository.cshl.edu/id/eprint/30697

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