Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach.

Anastasia Meshcheryakova,Martin Svoboda,Philip Zimmermann,Harald C Köfeler,Markus Jaritz,Georg Heinze,Christopher Gerner,Ammar Tahir,Alexander Triebl,Diana Mechtcheriakova,Felicitas Mungenast

doi:10.18632/oncotarget.7947

Abstract

The epithelial to mesenchymal transition (EMT) program is activated in epithelial cancer cells and facilitates their ability to metastasize based on enhanced migratory, proliferative, anti-apoptotic, and pluripotent capacities. Given the fundamental impact of sphingolipid machinery to each individual process, the sphingolipid-related mechanisms might be considered among the most prominent drivers/players of EMT; yet, there is still limited knowledge. Given the complexity of the interconnected sphingolipid system, which includes distinct sphingolipid mediators, their synthesizing enzymes, receptors and transporters, we herein apply an integrative approach for assessment of the sphingolipid-associated mechanisms underlying EMT program. We created the sphingolipid-/EMT-relevant 41-gene/23-gene signatures which were applied to denote transcriptional events in a lung cancer cell-based EMT model. Based on defined 35-gene sphingolipid/EMT-attributed signature of regulated genes, we show close associations between EMT markers, genes comprising the sphingolipid network at multiple levels and encoding sphingosine 1-phosphate (S1P)-/ceramide-metabolizing enzymes, S1P and lysophosphatidic acid (LPA) receptors and S1P transporters, pluripotency genes and inflammation-related molecules, and demonstrate the underlying biological pathways and regulators. Mass spectrometry-based sphingolipid analysis revealed an EMT-attributed shift towards increased S1P and LPA accompanied by reduced ceramide levels. Notably, using transcriptomics data across various cell-based perturbations and neoplastic tissues (24193 arrays), we identified the sphingolipid/EMT signature primarily in lung adenocarcinoma tissues; besides, bladder, colorectal and prostate cancers were among the top-ranked. The findings also highlight novel regulatory associations between influenza virus and the sphingolipid/EMT-associated mechanisms. In sum, data propose the multidimensional contribution of sphingolipid machinery to pathological EMT and may yield new biomarkers and therapeutic targets.

Highlights

The perception that lipids play critical roles in many aspects of cell regulation uncovers fundamentally novel mechanisms and pathways to interfere with upon dysregulation in distinct diseased conditions
The SPHK1driven effect(s) seems to play a dominant role in respect of sphingosine 1-phosphate (S1P) metabolism in A549-based epithelial to mesenchymal transition (EMT) process triggered by TGFbeta + TNFalpha and results in accumulation of intracellular S1P at the mesenchymal/fibroblast-like stage
This hypothesis is strengthened by recent data of Albinet et al [18], who defined principal role of SPHK1/S1P in melanoma-stroma interactions by showing that SPHK1active melanoma cells triggered the differentiation of fibroblasts to myofibroblasts and increased the production of matrix metalloproteinases

Summary

Introduction

The perception that lipids play critical roles in many aspects of cell regulation uncovers fundamentally novel mechanisms and pathways to interfere with upon dysregulation in distinct diseased conditions. Among the plethora of metabolites, S1P and Cer have emerged as potent mediators generally functioning with opposing biological effects, and the S1P/Cer rheostat is considered as one of the decisive cellular factors to drive either proliferation or apoptosis (reviewed in [4])

Methods

Results

Conclusion