Distinct Lipidomic Landscapes Associated with Clinical Stages of Urothelial Cancer of the Bladder

Danthasinghe Waduge Badrajee Piyarathna, Thekkelnaycke M. Rajendiran, Vasanta Putluri, Venkatrao Vantaku, Tanu Soni, Friedrich Carl von Rundstedt, Sri Ramya Donepudi, Feng Jin, Suman Maity, Chandrashekar Ambati, Jianrong Dong, Daniel Gödde, Stephan Roth, Stephan Störkel, Stephan Degener, George Michailidis, Seth P. Lerner, Subramaniam Pennathur, Yair Lotan, Cristian CoarfaArun Sreekumar, Nagireddy Putluri

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background: The first global lipidomic profiles associated with urothelial cancer of the bladder (UCB) and its clinical stages associated with progression were identified. Objective: To identify lipidomic signatures associated with survival and different clinical stages of UCB. Design, setting, and participants: Pathologically confirmed 165 bladder-derived tissues (126 UCB, 39 benign adjacent or normal bladder tissues). UCB tissues included Ta (n = 16), T1 (n = 30), T2 (n = 43), T3 (n = 27), and T4 (n = 9); lymphovascular invasion (LVI) positive (n = 52) and negative (n = 69); and lymph node status N0 (n = 28), N1 (n = 11), N2 (n = 9), N3 (n = 3), and Nx (n = 75). Results and limitations: UCB tissues have higher levels of phospholipids and fatty acids, and reduced levels of triglycerides compared with benign tissues. A total of 59 genes associated with altered lipids in UCB strongly correlate with patient survival in an UCB public dataset. Within UCB, there was a progressive decrease in the levels of phosphatidylserine (PS), phosphatidylethanolamines (PEs), and phosphocholines, whereas an increase in the levels of diacylglycerols (DGs) with tumor stage. Transcript and protein expression of phosphatidylserine synthase 1, which converts DGs to PSs, decreased progressively with tumor stage. Levels of DGs and lyso-PEs were significantly elevated in tumors with LVI and lymph node involvement, respectively. Lack of carcinoma in situ and treatment information is the limitation of our study. Conclusions: To date, this is the first study describing the global lipidomic profiles associated with UCB and identifies lipids associated with tumor stages, LVI, and lymph node status. Our data suggest that triglycerides serve as the primary energy source in UCB, while phospholipid alterations could affect membrane structure and/or signaling associated with tumor progression. Patient summary: Lipidomic alterations identified in this study set the stage for characterization of pathways associated with these altered lipids that, in turn, could inform the development of first-of-its-kind lipid-based noninvasive biomarkers and novel therapeutic targets for aggressive urothelial cancer of the bladder. Altered lipid metabolism, particularly metabolism of phospholipids and triglycerides, in clinical stages of bladder cancer lays the framework for understanding the biological basis of progression of urothelial cancer of the bladder, development of innovative lipid-based noninvasive markers for disease prognosis, and novel therapeutic regimens targeting lipid pathways.

Original languageEnglish (US)
JournalEuropean Urology Focus
DOIs
Publication statusAccepted/In press - 2017

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Keywords

  • Lymphovascular invasion
  • Phosphatidylserine synthase
  • Phospholipids
  • Triglycerides

ASJC Scopus subject areas

  • Urology

Cite this

Piyarathna, D. W. B., Rajendiran, T. M., Putluri, V., Vantaku, V., Soni, T., von Rundstedt, F. C., ... Putluri, N. (Accepted/In press). Distinct Lipidomic Landscapes Associated with Clinical Stages of Urothelial Cancer of the Bladder. European Urology Focus. https://doi.org/10.1016/j.euf.2017.04.005