{
"METABOLOMICS WORKBENCH":{"STUDY_ID":"ST002072","ANALYSIS_ID":"AN003377","VERSION":"1","CREATED_ON":"January 31, 2022, 2:28 pm"},

"PROJECT":{"PROJECT_TITLE":"A non-dividing population with high pyruvate dehydrogenase kinase activity drives metabolic heterogeneity and tumorigenesis in the intestine","PROJECT_SUMMARY":"Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in increased number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. More importantly, we found a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a highly heterogeneous feature of cancer, and more importantly, they indicate that this metabolic adaptation occurs in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.","INSTITUTE":"Massachusetts General Hospital","LAST_NAME":"Mostoslavsky","FIRST_NAME":"Raul","ADDRESS":"55 Fruit Street Boston, MA 02114","EMAIL":"rmostoslavsky@mgh.harvard.edu","PHONE":"617-643-3146"},

"STUDY":{"STUDY_TITLE":"A non-dividing population with high pyruvate dehydrogenase kinase activity drives metabolic heterogeneity and tumorigenesis in the intestine","STUDY_SUMMARY":"Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in increased number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. More importantly, we found a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a highly heterogeneous feature of cancer, and more importantly, they indicate that this metabolic adaptation occurs in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.","INSTITUTE":"Massachusetts General Hospital","DEPARTMENT":"Brigham and Women's Hospital","LAST_NAME":"Mostoslavsky","FIRST_NAME":"Raul","ADDRESS":"55 Fruit Street Boston, MA 02114","EMAIL":"rmostoslavsky@mgh.harvard.edu","PHONE":"5189653364"},

"SUBJECT":{"SUBJECT_TYPE":"Mammal","SUBJECT_SPECIES":"Mus musculus","TAXONOMY_ID":"10090"},
"SUBJECT_SAMPLE_FACTORS":[
{
"Subject ID":"-",
"Sample ID":"adenoma_colon_HCl_1",
"Factors":{"Treatment":"adenoma"},
"Additional sample data":{"RAW_FILE_NAME":"adenoma_colon_HCl_1-total ion count.imzML"}
},
{
"Subject ID":"-",
"Sample ID":"adenoma_dan_HCl_2",
"Factors":{"Treatment":"adenoma"},
"Additional sample data":{"RAW_FILE_NAME":"adenoma_dan_HCl_2-total ion count.imzML"}
},
{
"Subject ID":"-",
"Sample ID":"adenoma_dan_HCl_3",
"Factors":{"Treatment":"adenoma"},
"Additional sample data":{"RAW_FILE_NAME":"adenoma_dan_HCl_3-total ion count.imzML"}
}
],
"COLLECTION":{"COLLECTION_SUMMARY":"As stated in the paper: Colorectal tissue was stored at -80 °C until processing. Cryosections of the colorectal tissue, containing the adenoma, were taken at 10 µm thickness and were mounted on indium tin oxide (ITO) slides for MALDI MSI analysis. Serial sections were obtained for MALDI MSI and immunofluorescence microscopy using a pPDH antibody and DAPI staining. The cryosections used for immunofluorescence were 5 µm in thickness. Fluorescent microscopy images were acquired using a 40x objective (Zeiss Observer Z.1, Oberkochen, Germany), a DAPI filter (Filter Set 49, Carl Zeiss Microscopy, Oberkochen, Germany), and an FITC filter (31001, Chroma Technology Corporation, Bellows Falls, VT).","SAMPLE_TYPE":"Colon"},

"TREATMENT":{"TREATMENT_SUMMARY":"N/A"},

"SAMPLEPREP":{"SAMPLEPREP_SUMMARY":"As stated in the paper: 4.4 mg/mL of 1,5-diaminonapthalene hydrochloride (CAS: 2243-62-41, Sigma-Aldrich, Darnstadt, Germany) was dissolved in 4/4.5/0.5 HPLC grade water/ethanol/1 M HCl (v/v/v). 28 The 10 µm thick tissue sections were sprayed using a TM-sprayer (HTX Technologies, Chapel Hill, NC) in a four-pass method. The parameters of the matrix application set in the TM-sprayer were as follows: spray nozzle velocity (1200 mm/min), track spacing (2 mm), flow rate (0.09 mL/min), spray nozzle temperature (75 °C), and nitrogen gas pressure (10 psi)"},

"CHROMATOGRAPHY":{"CHROMATOGRAPHY_TYPE":"None (Direct infusion)","INSTRUMENT_NAME":"timsTOF fleX","COLUMN_NAME":"none"},

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

"MS":{"INSTRUMENT_NAME":"Bruker timsTOF fleX","INSTRUMENT_TYPE":"QTOF","MS_TYPE":"MALDI","ION_MODE":"NEGATIVE","MS_COMMENTS":"SCilS 2022a pro"},

"MS_METABOLITE_DATA":{
"Units":"Da",

"Data":[{"Metabolite":"fumarate","adenoma_colon_HCl_1":"70.9469147","adenoma_dan_HCl_2":"97.916687","adenoma_dan_HCl_3":"269.25971"},{"Metabolite":"Succinate","adenoma_colon_HCl_1":"13.7846333","adenoma_dan_HCl_2":"312.742577","adenoma_dan_HCl_3":"476.288666"},{"Metabolite":"a-ketoglutarate","adenoma_colon_HCl_1":"8.17143059","adenoma_dan_HCl_2":"20.8496666","adenoma_dan_HCl_3":"38.0566139"},{"Metabolite":"pentose phosphate","adenoma_colon_HCl_1":"29.6945839","adenoma_dan_HCl_2":"14.286932","adenoma_dan_HCl_3":"76.3336105"},{"Metabolite":"hexose phosphate","adenoma_colon_HCl_1":"400.424622","adenoma_dan_HCl_2":"116.034538","adenoma_dan_HCl_3":"258.387848"},{"Metabolite":"palmitoleic","adenoma_colon_HCl_1":"97.7862244","adenoma_dan_HCl_2":"40.3751869","adenoma_dan_HCl_3":"68.404213"},{"Metabolite":"oleic","adenoma_colon_HCl_1":"1341.27612","adenoma_dan_HCl_2":"272.815277","adenoma_dan_HCl_3":"299.874115"}],

"Metabolites":[{"metabolite_name":"fumarate"},{"metabolite_name":"Succinate"},{"metabolite_name":"a-ketoglutarate"},{"metabolite_name":"pentose phosphate"},{"metabolite_name":"hexose phosphate"},{"metabolite_name":"palmitoleic"},{"metabolite_name":"oleic"}]
}

}