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

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

doi:10.1186/s40170-017-0171-2

Abstract

BackgroundCancer 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.MethodsA 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.ResultsMetabolomic 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.ConclusionsUsing 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.

Highlights

Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites
The top metabolite predictions made by mummichog were glutamine, cytidine monophosphate (CMP), guanosine monophosphate (GMP), uridine monophosphate (UMP), citrate/isocitrate, and adenosine monophosphate (AMP)
We used an autonomous metabolomic workflow to uncover the metabolic differences between cancer cells in a primary tumor, and those that have metastasized to a distant organ

Summary

Introduction

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 modify their metabolism and metabolite production. The fraction of malignant cells that are shed from the primary tumor require traits that allow them to survive in circulation and colonize distant organs [1]. Cancer cells reprogram their microenvironment to assist tumor growth. The metabolism, growth, and survival of the metastatic cells are likely dependent on the attributes of the new site. Metabolites can be directly involved in increasing cancer cell growth, for example, succinate and fumarate are known to inhibit prolyl hydroxylase enzymes producing a pseudo-hypoxic state, driving glycolysis, and tumor proliferation [7]. Understanding the metabolism of cancer cells in a primary tumor versus those that have metastasized to a secondary organ site can reveal metabolic adaptions of a disseminating cancer cell

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