Oncotarget

Research Papers:

Imbalanced sphingolipid signaling is maintained as a core proponent of a cancerous phenotype in spite of metabolic pressure and epigenetic drift

Monique M.P. Speirs, Adam C. Swensen, Tsz Y. Chan, Peter M. Jones, John C. Holman, McCall B. Harris, John A. Maschek, James E. Cox, Richard H. Carson, Jonathon T. Hill, Joshua L. Andersen, John T. Prince, John C. Price _

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Oncotarget. 2019; 10:449-479. https://doi.org/10.18632/oncotarget.26533

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Abstract

Monique M.P. Speirs1,*, Adam C. Swensen1,*, Tsz Y. Chan1, Peter M. Jones1, John C. Holman1, McCall B. Harris1, John A. Maschek2, James E. Cox2, Richard H. Carson1, Jonathon T. Hill3, Joshua L. Andersen1, John T. Prince1 and John C. Price1

1Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA

2Health Sciences Cores-Metabolomics, University of Utah, Salt Lake, Utah, USA

3Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA

*These authors contributed equally to this work

Correspondence to:

John C. Price, email: JCPrice@chem.byu.edu

Keywords: multi-omics analysis of cancer; clonal evolution; metabolic reprogramming; sphingolipid signaling; sphingosine kinase

Received: September 13, 2018     Accepted: December 10, 2018     Published: January 11, 2019

ABSTRACT

Tumor heterogeneity may arise through genetic drift and environmentally driven clonal selection for metabolic fitness. This would promote subpopulations derived from single cancer cells that exhibit distinct phenotypes while conserving vital pro-survival pathways. We aimed to identify significant drivers of cell fitness in pancreatic adenocarcinoma (PDAC) creating subclones in different nutrient formulations to encourage differential metabolic reprogramming. The genetic and phenotypic expression profiles of each subclone were analyzed relative to a healthy control cell line (hTert-HPNE). The subclones exhibited distinct variations in protein expression and lipid metabolism. Relative to hTert-HPNE, PSN-1 subclones uniformly maintained modified sphingolipid signaling and specifically retained elevated sphingosine-1-phosphate (S1P) relative to C16 ceramide (C16 Cer) ratios. Each clone utilized a different perturbation to this pathway, but maintained this modified signaling to preserve cancerous phenotypes, such as rapid proliferation and defense against mitochondria-mediated apoptosis. Although the subclones were unique in their sensitivity, inhibition of S1P synthesis significantly reduced the ratio of S1P/C16 Cer, slowed cell proliferation, and enhanced sensitivity to apoptotic signals. This reliance on S1P signaling identifies this pathway as a promising drug-sensitizing target that may be used to eliminate cancerous cells consistently across uniquely reprogrammed PDAC clones.


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