Summary of Study ST002835

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001775. The data can be accessed directly via it's Project DOI: http://dx.doi.org/10.21228/M88M6V This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002835
Study TitleInvestigation of FGFR signaling controlled metabolism in FGFR2-fusion+ intrahepatic cholangiocarcinoma
Study SummaryGenomic alterations that activate FGFR2 are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to treatment with FGFR inhibitors. However, the depth and duration of responses are often limited. Elucidating the FGFR2-driven oncogenic program and the adaptions to FGFR inhibition is needed to gain insight into the biology of these tumors and inform future therapeutic development. Here, we conducted metabolomic analysis of patient-derived models to define the pathways that fuel tumor growth downstream of oncogenic FGFR2 signaling in ICC and to uncover compensatory mechanisms associated with pathway inhibition. We find FGFR2-fusion+ ICC maintains a highly glycolytic phenotype in FGFR2+ ICC. Conversely, FGFR inhibition blocks glucose uptake and glycolysis, while inciting a series of adaptive changes. Thus, we show that glycolysis is a key downstream effector of oncogenic FGFR2 signaling in ICC, and that pronounced metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.
Institute
Massachusetts General Hospital
Last NameZhen
First NameYuanli
Address185 cambridge street, room 4100
Emailyzhen1@mgh.harvard.edu
Phone4698792279
Submit Date2023-08-26
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2024-03-20
Release Version1
Yuanli Zhen Yuanli Zhen
http://dx.doi.org/10.21228/M88M6V
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR001775
Project DOI: http://dx.doi.org/10.21228/M88M6V
Project Title:FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma
Project Summary:Genomic alterations that activate FGFR2 are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibitor treatment. However, the depth and duration of responses are often limited. Here, we conducted integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define the pathways that fuel tumor growth downstream of oncogenic FGFR2 signaling in ICC and to uncover compensatory mechanisms associated with pathway inhibition. We find FGFR2-mediated activation of NF-kB maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting a series of adaptive changes, including switching fuel source utilization to favor fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-kB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.
Institute:mgh
Last Name:Zhen
First Name:Yuanli
Address:185 cambridge street, room 4100
Email:yzhen1@mgh.harvard.edu
Phone:4698792279

Subject:

Subject ID:SU002945
Subject Type:Cultured cells
Subject Species:Homo sapiens
Taxonomy ID:9606
Species Group:Mammals

Factors:

Subject type: Cultured cells; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id cell line treatment labeling status
SA307239SUB11589p2_Spl09ICC13-7 control 13C6-Glucose Isotopic tracing 0h as ctrl
SA307240SUB11589p2_Spl07ICC13-7 control 13C6-Glucose Isotopic tracing 0h as ctrl
SA307241SUB11589p2_Spl08ICC13-7 control 13C6-Glucose Isotopic tracing 0h as ctrl
SA307242SUB11589p2_Spl15ICC13-7 control 13C6-Glucose Isotopic tracing 1h
SA307243SUB11589p2_Spl14ICC13-7 control 13C6-Glucose Isotopic tracing 1h
SA307244SUB11589p2_Spl16ICC13-7 control 13C6-Glucose Isotopic tracing 1h
SA307245SUB11589p2_Spl20ICC13-7 control 13C6-Glucose Isotopic tracing 24h
SA307246SUB11589p2_Spl21ICC13-7 control 13C6-Glucose Isotopic tracing 24h
SA307247SUB11589p2_Spl22ICC13-7 control 13C6-Glucose Isotopic tracing 24h
SA307230SUB11589p2_Spl12ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 0h as ctrl
SA307231SUB11589p2_Spl10ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 0h as ctrl
SA307232SUB11589p2_Spl11ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 0h as ctrl
SA307233SUB11589p2_Spl17ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 1h
SA307234SUB11589p2_Spl18ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 1h
SA307235SUB11589p2_Spl19ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 1h
SA307236SUB11589p2_Spl24ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 24h
SA307237SUB11589p2_Spl25ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 24h
SA307238SUB11589p2_Spl23ICC13-7 Infigratinib 13C6-Glucose Isotopic tracing 24h
SA307248SUB11589p2_Spl32ICC21 Afatinib N/A
SA307249SUB11589p2_Spl33ICC21 Afatinib N/A
SA307250SUB11589p2_Spl34ICC21 Afatinib N/A
SA307251SUB11589p2_Spl36ICC21 Combo N/A
SA307252SUB11589p2_Spl37ICC21 Combo N/A
SA307253SUB11589p2_Spl35ICC21 Combo N/A
SA307257SUB11589p2_Spl28ICC21 control N/A
SA307258SUB11589p2_Spl26ICC21 control N/A
SA307259SUB11589p2_Spl27ICC21 control N/A
SA307254SUB11589p2_Spl29ICC21 Infigratinib N/A
SA307255SUB11589p2_Spl30ICC21 Infigratinib N/A
SA307256SUB11589p2_Spl31ICC21 Infigratinib N/A
Showing results 1 to 30 of 30

Collection:

Collection ID:CO002938
Collection Summary:1 million ICC cells were seeded in 6 cm dishes under indicated treatments with triplicates to identify metabolic characteristics. Fresh media was provided 2 hours before harvest. For metabolite collection, media was completely aspirated, and cells were washed with ice-cold saline quickly. After washing, fully remove saline and cells can be scrapped in 1 ml pre-cooled methanol (-20°C) with internal standards (Cambridge Isotope Laboratories, MSK-A2-1.2), and transferred to glass vials, stored at -80°C until extraction.
Sample Type:Tumor cells

Treatment:

Treatment ID:TR002954
Treatment Summary:ICC13-7 cells were treated with DMSO or 100 nM infigratinib for 24 hours, then labeled with 13C6-Glucose for indicated time points (0,1,24 hours). ICC21 cells were treated with DMSO, 100 nM infigratinib, 100 nM afatinib or combo for 24 hours.

Sample Preparation:

Sampleprep ID:SP002951
Sampleprep Summary:Samples were dried under N2 flow. Samples were resuspended in acetonitrile 50% in water. The volume was scaled to the biomass. 15ul was used for the lowest biomass, and all other were scaled accordingly. Standard mixes were prepared at 100uM and run after the samples to allow for identification of the targets

Combined analysis:

Analysis ID AN004631 AN004632
Analysis type MS MS
Chromatography type HILIC HILIC
Chromatography system Thermo Vanquish Thermo Vanquish
Column Thermo BETASIL Diol (150 x 2.1mm,5um) Thermo BETASIL Diol (150 x 2.1mm,5um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Orbitrap ID-X Tribrid Thermo Orbitrap ID-X Tribrid
Ion Mode POSITIVE NEGATIVE
Units area analyzed by Compound discoverer (counts x seconds) area analyzed by Compound discoverer (counts x seconds)

Chromatography:

Chromatography ID:CH003485
Instrument Name:Thermo Vanquish
Column Name:Thermo BETASIL Diol (150 x 2.1mm,5um)
Column Temperature:40
Flow Gradient:The LC program was as follow: starting at 93% B, to 40% B in 19 min, then to 0% B in 9 min, maintained at 0% B for 5 min, then back to 93% B in 3 min and re-equilibrated at 93% B for 9 min.
Flow Rate:The flow rate was maintained at 0.15 mL/min, except for the first 30 seconds where the flow rate was uniformly ramped from 0.05 to 0.15 mL/ min.
Solvent A:20 mMAmmonium Carbonate, 0.1% Ammonium hydroxide, in Water
Solvent B:Acetonitrile 97%, in water
Chromatography Type:HILIC

MS:

MS ID:MS004378
Analysis ID:AN004631
Instrument Name:Thermo Orbitrap ID-X Tribrid
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Data was acquired on the ID-X in switching polarities at 120000 resolution, with an AGC target of 1e5, and a m/z range of 65 to 1000. MS1 data is acquired in switching polarities for all samples. Data is analyzed in Compound Discoverer 3.3 (CD, ThermoFisher Scientific). A mix of standard of each target was run along the samples and used as the unlabeled reference for the CD labelling workflow. Isotopomer distribution is found in the exchange column, as % of 0 labelled carbon, 1 labelled carbon, 2 labelled carbon, etc. Those are corrected for natural abundance. For the compounds that couldn’t be analyzed by CD, the areas have been extracted with Tracefinder manually.
Ion Mode:POSITIVE
  
MS ID:MS004379
Analysis ID:AN004632
Instrument Name:Thermo Orbitrap ID-X Tribrid
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Data was acquired on the ID-X in switching polarities at 120000 resolution, with an AGC target of 1e5, and a m/z range of 65 to 1000. Data is analyzed in Compound Discoverer 3.3 (CD, ThermoFisher Scientific). A mix of standard of each target was run along the samples and used as the unlabeled reference for the CD labelling workflow. Isotopomer distribution is found in the exchange column, as % of 0 labelled carbon, 1 labelled carbon, 2 labelled carbon, etc. Those are corrected for natural abundance. For the compounds that couldn’t be analyzed by CD, the areas have been extracted with Tracefinder manually.
Ion Mode:NEGATIVE
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