title: Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors.
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.
authors.affiliation: Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080;
authors.forename: Anneleen
authors.initials: A
authors.lastname: Daemen
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Nisebita
authors.initials: N
authors.lastname: Sahu
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Ron
authors.initials: R
authors.lastname: McCord
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Du
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Bonnie
authors.initials: B
authors.lastname: Liu
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kowanetz
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hong
authors.affiliation: Biochemical Pharmacology, Genentech, South San Francisco, CA 94080.
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Aaron
authors.initials: A
authors.lastname: Boudreau
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Rana
authors.initials: R
authors.lastname: Mroue
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Laura
authors.initials: L
authors.lastname: Corson
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Jing
authors.initials: J
authors.lastname: Qing
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Robert
authors.initials: R
authors.lastname: Yauch
authors.affiliation: Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080;
authors.forename: Gerard
authors.initials: G
authors.lastname: Manning
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.affiliation: Translational Oncology, Genentech, South San Francisco, CA 94080;
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, CA 94080; evangelista.marie@gene.com.
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000145:classification* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D050155:Lipogenesis / Q000235:genetics; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D055442:Metabolome / Q000235:genetics; D055432:Metabolomics; D015203:Reproducibility of Results; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D005973:Glutamine; D005947:Glucose
keywords: biomarkers for metabolic inhibitors; glycolysis; lipid synthesis; metabolic subtypes in PDAC; metabolite profiling