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| Status |
Public on Apr 30, 2012 |
| Title |
Kras is required for pancreatic tumor maintenance through regulation of hexosamine biosynthesis and the non-oxidative pentose phosphate pathway |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Ying H, Hua S, DePinho R |
| Citation(s) |
22541435 |
| |
| Submission date |
Sep 21, 2011 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Sujun Hua |
| E-mail(s) |
shua@mdanderson.org
|
| Organization name |
MD Anderson Cancer Center
|
| Lab |
Ronald DePinho Lab
|
| Street address |
1901 East Rd
|
| City |
Houston |
| State/province |
Tx |
| ZIP/Postal code |
77054 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (33)
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| Relations |
| BioProject |
PRJNA147317 |
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