Defining the landscape of metabolic dysregulations in cancer metastasis

Sara Abdul Kader,Karsten Suhre,Anna Halama,Gaurav Thareja,Shaima Dib,Arash Rafii,Iman W Achkar

doi:10.1007/s10585-021-10140-9

Abstract

Metastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies. However, the metabolic signatures of metastatic cells remain vastly elusive. Our aim was to determine metabolic dysregulations associated with high metastatic potential in breast cancer cell lines. We have selected 5 triple negative breast cancer (TNBC) cell lines including three with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and two with low metastatic potential (LMP) (BT549, HCC1143). The normal epithelial breast cell line (hTERT-HME1) was also investigated. The untargeted metabolic profiling of cells and growth media was conducted and total of 479 metabolites were quantified. First we characterized metabolic features differentiating TNBC cell lines from normal cells as well as identified cell line specific metabolic fingerprints. Next, we determined 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.

Highlights

Metastatic disease accounts for approximately 90% of cancer related deaths [1, 2], despite relatively low metastatic efficiency due to the challenging multistep cascade required to establish colonies in distant tissue [3]
We investigated metabolic differences between 5 triple negative breast cancer cell lines (BT549, HCC1143, MDAMB-231, MDA-MB-436, and MDA-MB-468) and normal breast cell line hTERT-HME1 using untargeted broad metabolic profiling
The clear separation, which can be seen between Triple negative breast cancer (TNBC) and control cells, on the principal component analysis (PCA) score plots (Supplementary Fig. 1, Fig. 1A), suggest strong metabolic differences between normal and cancer cells

Summary

Introduction

Metastatic disease accounts for approximately 90% of cancer related deaths [1, 2], despite relatively low metastatic efficiency due to the challenging multistep cascade required to establish colonies in distant tissue [3]. Triple negative breast cancer (TNBC), characterized by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) [4], tends to display a more aggressive clinical course with frequent distant recurrence and poor prognosis compared to other breast cancer types [5]. Lack of available targeted therapy for TNBC patients along with the limited understanding of the molecular processes governing metastatic disease reflect on very narrow treatment options for those patients [6]. Further insights into molecular events related to metastasis could revel novel treatment targets. The metabolic signatures discriminating healthy from disease are frequently deployed for biomarkers identification and to provide insights into the pathological processes causing disease [8,9,10]

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Conclusion