Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

Anneleen Daemen, David Peterson, Nisebita Sahu, Ron McCord, Xiangnan Du, Bonnie Liu, Katarzyna Kowanetz, Rebecca Hong, John Moffat, Min Gao, Aaron Boudreau, Rana Mroue, Laura Corson, Thomas O'Brien, Jing Qing, Deepak Sampath, Mark Merchant, Robert Yauch, Gerard Manning, Jeffrey SettlemanGeorgia Hatzivassiliou, Marie Evangelista, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

234 Scopus citations

Abstract

Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors.

Original languageEnglish (US)
Pages (from-to)E4410-E4417
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number32
DOIs
StatePublished - Aug 11 2015

Keywords

  • Biomarkers for metabolic inhibitors
  • Glycolysis
  • Lipid synthesis
  • Metabolic subtypes in PDAC
  • Metabolite profiling

ASJC Scopus subject areas

  • General

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