TY - JOUR
T1 - Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors
AU - Daemen, Anneleen
AU - Peterson, David
AU - Sahu, Nisebita
AU - McCord, Ron
AU - Du, Xiangnan
AU - Liu, Bonnie
AU - Kowanetz, Katarzyna
AU - Hong, Rebecca
AU - Moffat, John
AU - Gao, Min
AU - Boudreau, Aaron
AU - Mroue, Rana
AU - Corson, Laura
AU - O'Brien, Thomas
AU - Qing, Jing
AU - Sampath, Deepak
AU - Merchant, Mark
AU - Yauch, Robert
AU - Manning, Gerard
AU - Settleman, Jeffrey
AU - Hatzivassiliou, Georgia
AU - Evangelista, Marie
AU - DePinho, Ronald A.
PY - 2015/8/11
Y1 - 2015/8/11
N2 - 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.
AB - 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.
KW - Biomarkers for metabolic inhibitors
KW - Glycolysis
KW - Lipid synthesis
KW - Metabolic subtypes in PDAC
KW - Metabolite profiling
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U2 - 10.1073/pnas.1501605112
DO - 10.1073/pnas.1501605112
M3 - Article
C2 - 26216984
AN - SCOPUS:84938940583
SN - 0027-8424
VL - 112
SP - E4410-E4417
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
ER -