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Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2015 Aug 11; Vol. 112 (32), pp. E4410-7. Date of Electronic Publication: 2015 Jul 27. - Publication Year :
- 2015
-
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.
- Subjects :
- Adenocarcinoma genetics
Adenocarcinoma pathology
Biomarkers, Tumor metabolism
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal pathology
Cell Proliferation
Glucose metabolism
Glutamine metabolism
Glycolysis genetics
Humans
Inhibitory Concentration 50
Lipogenesis genetics
Mesoderm metabolism
Mesoderm pathology
Reproducibility of Results
Transcription, Genetic
Adenocarcinoma classification
Adenocarcinoma metabolism
Carcinoma, Pancreatic Ductal classification
Carcinoma, Pancreatic Ductal metabolism
Metabolome genetics
Metabolomics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 112
- Issue :
- 32
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 26216984
- Full Text :
- https://doi.org/10.1073/pnas.1501605112