Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids

Caroline H. Johnson, Antonio F. Santidrian, Sarah E. LeBoeuf, Michael E. Kurzy, Nicholas Rattray, Zahra Rattray, Benedikt Warth, Melissa Ritland, Linh T. Hoang, Celine Loriot, Jason Higa, James E. Hansen, Brunhilde H. Felding, Gary Siuzdak

Research output: Contribution to journalArticle

Abstract

Background -- Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.

Methods -- A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An “autonomous” mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.

Results -- Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.

Conclusions -- Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.
LanguageEnglish
JournalCancer and Metabolism
Volume5
Issue number1
DOIs
Publication statusPublished - 31 Oct 2017

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Metabolomics
Phospholipids
Neoplasm Metastasis
Neoplasms
Adipose Tissue
Breast
Lung
Workflow
cholesteryl sulfate
Phosphatidylglycerols
Metabolic Networks and Pathways
Heterografts
Mass Spectrometry
RNA
DNA

Keywords

  • cancer cells
  • metabolomics
  • cholesterol sulfate
  • phospholipids
  • tumour cells

Cite this

Johnson, Caroline H. ; Santidrian, Antonio F. ; LeBoeuf, Sarah E. ; Kurzy, Michael E. ; Rattray, Nicholas ; Rattray, Zahra ; Warth, Benedikt ; Ritland, Melissa ; Hoang, Linh T. ; Loriot, Celine ; Higa, Jason ; Hansen, James E. ; Felding, Brunhilde H. ; Siuzdak, Gary. / Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids. In: Cancer and Metabolism. 2017 ; Vol. 5, No. 1.
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abstract = "Background -- Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.Methods -- A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An “autonomous” mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.Results -- Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.Conclusions -- Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.",
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Johnson, CH, Santidrian, AF, LeBoeuf, SE, Kurzy, ME, Rattray, N, Rattray, Z, Warth, B, Ritland, M, Hoang, LT, Loriot, C, Higa, J, Hansen, JE, Felding, BH & Siuzdak, G 2017, 'Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids' Cancer and Metabolism, vol. 5, no. 1. https://doi.org/10.1186/s40170-017-0171-2

Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids. / Johnson, Caroline H.; Santidrian, Antonio F.; LeBoeuf, Sarah E.; Kurzy, Michael E.; Rattray, Nicholas; Rattray, Zahra; Warth, Benedikt; Ritland, Melissa; Hoang, Linh T.; Loriot, Celine; Higa, Jason; Hansen, James E.; Felding, Brunhilde H.; Siuzdak, Gary.

In: Cancer and Metabolism, Vol. 5, No. 1, 31.10.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids

AU - Johnson, Caroline H.

AU - Santidrian, Antonio F.

AU - LeBoeuf, Sarah E.

AU - Kurzy, Michael E.

AU - Rattray, Nicholas

AU - Rattray, Zahra

AU - Warth, Benedikt

AU - Ritland, Melissa

AU - Hoang, Linh T.

AU - Loriot, Celine

AU - Higa, Jason

AU - Hansen, James E.

AU - Felding, Brunhilde H.

AU - Siuzdak, Gary

PY - 2017/10/31

Y1 - 2017/10/31

N2 - Background -- Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.Methods -- A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An “autonomous” mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.Results -- Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.Conclusions -- Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.

AB - Background -- Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.Methods -- A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An “autonomous” mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.Results -- Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.Conclusions -- Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.

KW - cancer cells

KW - metabolomics

KW - cholesterol sulfate

KW - phospholipids

KW - tumour cells

U2 - 10.1186/s40170-017-0171-2

DO - 10.1186/s40170-017-0171-2

M3 - Article

VL - 5

JO - Cancer and Metabolism

T2 - Cancer and Metabolism

JF - Cancer and Metabolism

SN - 2049-3002

IS - 1

ER -