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

Cancer & Metabolism

Nicholas J. W. Rattray¹  Melissa Ritland²  Jason Higa²  Celine Loriot²  Sarah E. LeBoeuf²  Antonio F. Santidrian²  Brunhilde H. Felding²  Zahra Rattray³  Michael E. Kurczy⁴  Linh T. Hoang⁴  Gary Siuzdak⁴  Benedikt Warth⁴  Caroline H. Johnson⁴  James E. Hansen⁵ 

[1] Department of Environmental Health Sciences, Yale School of Public HealthYale School of Medicine;Department of Molecular and Experimental Medicine, The Scripps Research Institute;Department of Therapeutic Radiology, Yale School of Medicine, Yale University;Scripps Center for Metabolomics, The Scripps Research Institute;Yale Cancer Center, Yale School of Medicine;

关键词: Cancer;    Cholesterol sulfate;    Phospholipids;    Autonomous metabolomics;    Mummichog;    Metastasis;   

DOI  :  10.1186/s40170-017-0171-2

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown