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

doi:10.18632/oncotarget.26533

Monique M.P Speirs, John A Maschek + Show 11 more

Open Access

https://doi.org/10.18632/oncotarget.26533

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Journal: Oncotarget	Publication Date: Jan 11, 2019
Citations: 6	License type: cc-by

Affiliation: Brigham Young University, University of Utah

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.

Highlights

Cancer development is a highly dynamic biochemical process driven by both neutral evolution and environmental pressure [1]
We propose that the selective pressure to maintain rapid growth and apoptotic resistance promotes this shift in Sphingosine Kinase 1 (SK1)-mediated S1P/C16 ceramide (C16 Cer) metabolism because it is a significant component of metabolic reprogramming in human pancreatic cancer cells
We identified several enzymes directly involved in perturbing the S1P/C16 Cer lipid ratio by RNA-Seq, including Acid Ceramidase (ACdase), Neutral Ceramidase (N-Cdase), Ceramide Synthase 5 (Cers5), S1P Phosphatases 1 and 2 (SPPases 1 and 2), S1P Lyase 1 (S1PL1), and Sphingosine Kinases 1 and 2 (Figure 5B)

Summary

Introduction

Cancer development is a highly dynamic biochemical process driven by both neutral evolution and environmental pressure [1]. Due to the combined influences of stochastic and selective factors, like genetic instability and metabolic stress, a single originating cancer cell can give rise to heterogeneous clonal populations with distinct genetic and/or phenotypic profiles [2]. Inter- and intra-tumor heterogeneity promote drug resistance and limit the predictability of cancer prognosis [3,4,5]. Multiple subclones may exhibit parallel evolution, whereby specific adaptations or pro-cancer pathways are selectively maintained throughout tumor progression [6]. Conserved pathways provide a degree of evolutionary predictability [3] and potentially serve as ubiquitous drug targets among heterogeneous cancer subclones [7, 8]. Predicting which pathways are retained so that different subclones will consistently respond to treatments, versus those which are frequently divergent, remains limited in most tumor types [3]

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