{
"METABOLOMICS WORKBENCH":{"STUDY_ID":"ST002999","ANALYSIS_ID":"AN004926","VERSION":"1","CREATED_ON":"December 7, 2023, 9:55 am"},

"PROJECT":{"PROJECT_TITLE":"Metabolic Reprogramming by Histone Deacetylase Inhibition Preferentially Targets NRF2-activated tumors","PROJECT_SUMMARY":"Interplay between metabolism and chromatin signaling are implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association is observed across cultured cells, mouse models and patient-derived xenografts. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.","INSTITUTE":"Columbia University Medical Center","DEPARTMENT":"Genetics and Development","LABORATORY":"Chao Lu","LAST_NAME":"Karagiannis","FIRST_NAME":"Dimitris","ADDRESS":"630 West 168th Street, NEW YORK, NY, 10032, USA","EMAIL":"karagiannis_dimitrios@yahoo.gr","PHONE":"+30 6982804931"},

"STUDY":{"STUDY_TITLE":"Metabolomics and glucose and glutamine labeled isotope tracing analysis in murine lung adenocarcinoma cells in the context of normal or active NRF2 pathway as well as HDAC and glutaminase inhibitor treatment.","STUDY_SUMMARY":"Interplay between metabolism and chromatin signaling are implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association is observed across cultured cells, mouse models and patient-derived xenografts. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors. In this metabolomics experiment we characterize the changes in metabolic pathway flux in KP LUAD cells in response to HDAC and glutaminase inhibition. This dataset includes metabolomics of U-C13 glucose tracing (1h and 24h) and U-C13 glutamine (8h) of mouse LUAD cell lines with Kras overexpression and p53 knock-out (KP), carrying empty vector (EV) or overexpression of NRF2dNeh2 (NRF2) and treated with DMSO, Romidepsin or CB-839. 3 technical replicates were done per condition in 2 separate experiments, 1: glucose tracing and 2: glutamine tracing.","INSTITUTE":"Columbia University - Medical Center","DEPARTMENT":"Genetics and Development","LABORATORY":"Chao Lu","LAST_NAME":"Dimitris","FIRST_NAME":"Karagiannis","ADDRESS":"622 W 168th St, New York, NY 10032","EMAIL":"karagiannis_dimitrios@yahoo.gr","PHONE":"+30 6982804931"},

"SUBJECT":{"SUBJECT_TYPE":"Cultured cells","SUBJECT_SPECIES":"Mus musculus","TAXONOMY_ID":"10090"},
"SUBJECT_SAMPLE_FACTORS":[
{
"Subject ID":"NA",
"Sample ID":"blank1",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"blank1.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"blank2",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"blank2.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"blank3",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"blank3.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"blank4",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"blank4.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_CB839_Gln_1",
"Factors":{"Genotype":"Empty vector","Treatment":"CB-839","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_CB839_Gln_1.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_CB839_Gln_2",
"Factors":{"Genotype":"Empty vector","Treatment":"CB-839","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_CB839_Gln_2.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_CB839_Gln_3",
"Factors":{"Genotype":"Empty vector","Treatment":"CB-839","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_CB839_Gln_3.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_1h_1",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_DMSO_1h_1.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_1h_2",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_DMSO_1h_2.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_1h_3",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_DMSO_1h_3.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_24h_1",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_DMSO_24h_1.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_24h_2",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_DMSO_24h_2.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_24h_3",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_DMSO_24h_3.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_Gln_1",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_DMSO_Gln_1.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_Gln_2",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_DMSO_Gln_2.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_DMSO_Gln_3",
"Factors":{"Genotype":"Empty vector","Treatment":"DMSO","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_DMSO_Gln_3.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_Rom_1h_1",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_Rom_1h_1.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_Rom_1h_2",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_Rom_1h_2.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_Rom_1h_3",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_Rom_1h_3.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_Rom_24h_1",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_Rom_24h_1.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_Rom_24h_2",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_Rom_24h_2.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_Rom_24h_3",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"EV_Rom_24h_3.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_ROM_Gln_1",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_ROM_Gln_1.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_ROM_Gln_2",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_ROM_Gln_2.mzML"}
},
{
"Subject ID":"KP_EV",
"Sample ID":"EV_ROM_Gln_3",
"Factors":{"Genotype":"Empty vector","Treatment":"Romidepsin","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"EV_ROM_Gln_3.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_CB839_Gln_1",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"CB-839","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_CB839_Gln_1.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_CB839_Gln_2",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"CB-839","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_CB839_Gln_2.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_CB839_Gln_3",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"CB-839","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_CB839_Gln_3.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_1h_1",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_DMSO_1h_1.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_1h_2",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_DMSO_1h_2.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_1h_3",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_DMSO_1h_3.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_24h_1",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_DMSO_24h_1.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_24h_2",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_DMSO_24h_2.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_24h_3",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_DMSO_24h_3.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_Gln_1",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_DMSO_Gln_1.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_Gln_2",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_DMSO_Gln_2.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_DMSO_Gln_3",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"DMSO","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_DMSO_Gln_3.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_Rom_1h_1",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_Rom_1h_1.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_Rom_1h_2",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_Rom_1h_2.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_Rom_1h_3",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"1 hour","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_Rom_1h_3.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_Rom_24h_1",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_Rom_24h_1.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_Rom_24h_2",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_Rom_24h_2.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_Rom_24h_3",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"24 hours","Tracer":"U-C13 Glucose"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"NRF2_Rom_24h_3.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_ROM_Gln_1",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_ROM_Gln_1.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_ROM_Gln_2",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_ROM_Gln_2.mzML"}
},
{
"Subject ID":"KP_NRF2",
"Sample ID":"NRF2_ROM_Gln_3",
"Factors":{"Genotype":"NRF2 overexpression","Treatment":"Romidepsin","Timepoint":"8 hours","Tracer":"U-C13 Glutamine"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"NRF2_ROM_Gln_3.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC_1",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"QC_1.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC_2",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"QC_2.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC_3",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"QC_3.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC_4",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"QC_4.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC1",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"QC1.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC2",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"QC2.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC3",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"QC3.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC4",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"QC4.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"QC5",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"1_20211110","RAW_FILE_NAME":"QC5.mzML"}
},
{
"Subject ID":"NA",
"Sample ID":"Blank_1",
"Factors":{"Genotype":"NA","Treatment":"NA","Timepoint":"NA","Tracer":"NA"},
"Additional sample data":{"Experiment":"2_20220428","RAW_FILE_NAME":"Blank_1.mzML"}
}
],
"COLLECTION":{"COLLECTION_SUMMARY":"Mouse lung adenocarcinoma (LUAD) cell lines were established as in a previous study by the Papagiannakopoulos lab (Romero et al. Nature Medicine 2017). Briefly, KrasLSL-G12D/+; p53flox/flox genetically engineered mice were intratracheally infected with pSECC lentiviral vectors expressing sgRNAs against Keap1 or tdTomato as a control. The mice developed LUAD tumors and cell lines were derived from them. In this experiment we used a cell line derived from control tumors (KP: Kras-mutant, p53-null). In this cell line we overexpressed an active form of NRF2 (NRF2) or introduced the empty vector (EV).","SAMPLE_TYPE":"Cultured cells"},

"TREATMENT":{"TREATMENT_SUMMARY":"For glucose tracing analysis, 2x105 KP cells (n=3) were plated in 6-well plates overnight in RPMI medium (Sigma). After 24 hours, the media was replaced with fresh RPMI medium containing DMSO or Romidepsin. At 48 hours the media was replaced with fresh glucose-free RPMI medium (Sigma) containing 10% dialyzed fetal bovine serum (Gibco), 2.0 g/L 13C6-glucose (Sigma) and DMSO or 5nM Romidepsin. Cells were harvested at 49 and 72 hours and processed as described below. For glutamine tracing, 2x105 KP cells (n=3) were plated in 6-well plates overnight in RPMI medium (Sigma). After 24 hours, the media was replaced with fresh RPMI medium containing DMSO, 1nM Romidepsin or 150nM CB-839. At 48 hours the media was replaced with fresh glutamine-free RPMI medium (Sigma) containing 10% dialyzed fetal bovine serum (Gibco), 2.0 g/L 13C6-glutamine (Cambridge Isotope Laboratories) and DMSO, 1nM Romidepsin or 150nM CB-839"},

"SAMPLEPREP":{"SAMPLEPREP_SUMMARY":"Cells were washed with cold PBS, lysed in 80% Ultra LC-MS acetonitrile (Thermo Scientific) supplemented with 20 µM deuterated 2-hydroxyglutarate (D-2-hydroxyglutaric-2,3,3,4,4-d5 acid (d5-2HG), Cambridge Isotope Laboratories) as an internal standard on ice for 15 minutes, and centrifuged for 10 minutes at 20,000 x g at 4 °C. 200 µL of supernatants were subjected to mass spectrometry analysis."},

"CHROMATOGRAPHY":{"CHROMATOGRAPHY_TYPE":"HILIC","INSTRUMENT_NAME":"Agilent 1290 Infinity","COLUMN_NAME":"Merck SeQuant ZIC-HILIC (150 x 2.1mm,5um)","SOLVENT_A":"25 mM ammonium carbonate in water","SOLVENT_B":"acetonitrile","FLOW_GRADIENT":"0-1.5 min, 80% B; 1.5-7 min, 80% B to 50% B, 7-8.5 min, 50% B; 8.5-8.7 min, 50% B to 80% B, 8.7-13 min, 80% B","FLOW_RATE":"0.3 mL/min","COLUMN_TEMPERATURE":"35"},

"ANALYSIS":{"ANALYSIS_TYPE":"MS"},

"MS":{"INSTRUMENT_NAME":"Agilent 6545 QTOF","INSTRUMENT_TYPE":"QTOF","MS_TYPE":"ESI","ION_MODE":"NEGATIVE","MS_COMMENTS":"The overall runtime was 13 minutes, and the injection volume was 5 µL. The Agilent Q-TOF was operated in negative mode and the relevant parameters were as listed: ion spray voltage, 3500 V; nozzle voltage, 1000 V; fragmentor voltage, 125 V; drying gas flow, 11 L/min; capillary temperature, 325 °C; drying gas temperature, 350 °C; and nebulizer pressure, 40 psi. A full scan range was set at 50 to 1600 (m/z). The reference masses were 119.0363 and 980.0164. The acquisition rate was 2 spectra/s. Targeted analysis, isotopologues extraction (for the metabolic tracing study), and natural isotope abundance correction were performed by the Agilent Profinder B.10.00 Software (Agilent Technologies)."},

"MS_METABOLITE_DATA":{
"Units":"Abundance (Extracted ion chromatogram core area)",

"Data":[{"Metabolite":"Citric 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"Metabolites":[{"Metabolite":"Citric acid","PubChem":"311","KEGG":"C00158","Tgt RT":"12.5","Expected m/z":"191.0197"},{"Metabolite":"L-Glutamate","PubChem":"33032","KEGG":"C00025","Tgt RT":"7.55","Expected m/z":"NA"},{"Metabolite":"Fumaric acid","PubChem":"444972","KEGG":"C00122","Tgt RT":"9","Expected m/z":"115.0037"},{"Metabolite":"L-Malic acid","PubChem":"222656","KEGG":"C00149","Tgt RT":"9","Expected m/z":"NA"},{"Metabolite":"Succinic acid","PubChem":"1110","KEGG":"C00042","Tgt RT":"7","Expected m/z":"117.0193"},{"Metabolite":"Oxoglutaric acid","PubChem":"51","KEGG":"C00026","Tgt RT":"7.2","Expected m/z":"145.01373"},{"Metabolite":"Pyruvate","PubChem":"1060","KEGG":"C00022","Tgt RT":"1.5","Expected m/z":"87.00088"},{"Metabolite":"Uridine triphosphate (UTP)","PubChem":"6133","KEGG":"C00075","Tgt RT":"12.6","Expected m/z":"NA"},{"Metabolite":"Adenosine triphosphate (ATP)","PubChem":"5957","KEGG":"C00002","Tgt RT":"12.5","Expected m/z":"505.9885"},{"Metabolite":"L-Lactic acid","PubChem":"107689","KEGG":"C00186","Tgt RT":"2.44","Expected m/z":"89.0244"},{"Metabolite":"L-Serine","PubChem":"5951","KEGG":"C00065","Tgt RT":"7.6","Expected m/z":"NA"},{"Metabolite":"D-Glyceraldehyde 3-phosphate","PubChem":"3418","KEGG":"C00118","Tgt RT":"10.873","Expected m/z":"NA"},{"Metabolite":"D-Glycerate 3-phosphate","PubChem":"439183","KEGG":"C00197","Tgt RT":"11","Expected m/z":"NA"},{"Metabolite":"D-Glucose 6-phosphate","PubChem":"5958","KEGG":"C00092","Tgt RT":"11.5","Expected m/z":"NA"},{"Metabolite":"Guanosine triphosphate (GTP)","PubChem":"6830","KEGG":"C00044","Tgt RT":"13.5","Expected m/z":"521.9834"},{"Metabolite":"L-Glutamine","PubChem":"5961","KEGG":"C00064","Tgt RT":"8.44","Expected m/z":"145.0619"}]
}

}