Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

Abstract

SUMMARY 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 KrasG12D-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on KrasG12D expression. Transcriptome and metabolomic analyses indicate that KrasG12D 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 KrasG12D 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.

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

“…Our findings, that a glycolysis gene signature is specifically upregulated in KRAS-mutant lung tumors and that KRAS-mutant cells are more sensitive to the glycolysis inhibitor 2-DG, are consistent with such changes in tumor metabolism. Moreover, a recent report showed that KRAS can also regulate glycolysis and glucose metabolism in a pancreatic cancer mouse model (39). Our observations, however, show that in other cancer types, such as colon cancer, KRAS-mutant tumors do not display elevated dependence on glycolysis.…”

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

“…19,39,40 Furthermore; Ras is known to promote an autophagic response. 19,22 We observed increased basal levels of microtubule-associated protein1 lightchain3 (LC3) in EcdCRas overexpressing hMECs under nutrition deprivation conditions. Indeed, immunofluorescence analyses showed increased LC3 puncta 24 in EcdCRas overexpressing hMECs (Fig.…”

“…LC3 may accumulate in cells through stabilization of protein due to reduced lysosomal turnover or by upregulation of transcription. 20,[22][23][24][25][26] Recent reports suggest that LC3 is transcriptionally regulated by the activation of pathways downstream of Ras. 41,42 We observed significantly higher levels of LC3B mRNA expression, suggesting a possible role of Ecd plus Ras to upregulate basal autophagy.…”

“…18 Given that recent studies have demonstrated that oncogenic H-Ras or K-Ras promotes basal autophagy as a mechanism to promote tumor cell survival, [19][20][21][22] we assessed if EcdCRas promote cell survival under nutrient deprivation by elevating autophagy markers.…”

Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

“…The high prevalence of activating KRAS mutations in PDAC tumors and apparent KRAS oncogene addiction in pancreatic tumors (39) (40) emphasizes the importance of identifying anti-Ras therapies in the treatment of pancreatic cancer patients. Studies demonstrated the importance of RalA and, more specifically, phosphorylation at S194 by AAK, in tumor development (6, 7, 10).…”