Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism Academic Article uri icon

Overview

MeSH Major

  • Adenocarcinoma
  • Disease Models, Animal
  • Pancreatic Neoplasms
  • Proto-Oncogene Proteins p21(ras)

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┬ávivo 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.

publication date

  • April 27, 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3472002

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2012.01.058

PubMed ID

  • 22541435

Additional Document Info

start page

  • 656

end page

  • 70

volume

  • 149

number

  • 3