title: Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
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.
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Sujun
authors.initials: S
authors.lastname: Hua
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Eliot
authors.initials: E
authors.lastname: Fletcher-Sananikone
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Coloff
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Andrea
authors.initials: A
authors.lastname: Viale
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Ji-hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Carol
authors.initials: C
authors.lastname: Lim
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Guimaraes
authors.forename: Eric S
authors.initials: ES
authors.lastname: Martin
authors.forename: Jeffery
authors.initials: J
authors.lastname: Chang
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Perry
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)