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

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.

Correlating basal gene expression across chemical sensitivity data to screen for novel synergistic interactors of HDAC inhibitors in pancreatic carcinoma

“…22,23 Additionally, Speirs et al identified SPHK1 as a key driver of the conserved S1P: Ceramide imbalance in pancreatic cancer subcultures and therefore one of the central controlling hubs of rheostat machinery. 22 The most recent literature data suggested that sphingolipid signaling pathway could be an important novel therapeutic target to suppress proliferation across pancreatic tumors made up of heterogeneous cell populations, with recognition of potential of SPHK1 inhibitors as an approach to reverse healthy balance of pro-and anti-apoptotic signaling in pancreatic cancers. 22,[24][25][26] Additionally, predictions identified synergism between pan-HDAC inhibitor and SPHK1 inhibitor to be highly scored (in first 5% of the ordered list of predictions) (Table 1 and Supplementary Data File 1).…”

“…Sphingolipid rheostat, and particularly equilibrium between ceramide and S1P, have been just recently characterized as one of the critical regulator of pro-and anti-apoptotic singling in metabolically dynamic pancreatic cancers. 22,23 Additionally, Speirs et al…”

“…22 The most recent literature data suggested that sphingolipid signaling pathway could be an important novel therapeutic target to suppress proliferation across pancreatic tumors made up of heterogeneous cell populations, with recognition of potential of SPHK1 inhibitors as an approach to reverse healthy balance of pro-and anti-apoptotic signaling in pancreatic cancers. 22,[24][25][26] Additionally, predictions identified synergism between pan-HDAC inhibitor and SPHK1 inhibitor to be highly scored (in first 5% of the ordered list of predictions) (Table 1 and Supplementary Data File 1). To further corroborate our results on potential synergism occurring between HDACi and sphingolipid signaling pathway in pancreatic carcinoma, expression analysis was performed on data obtained from pancreatic cancer cohort (The Cancer Genome Atlas (TCGA) database -number of samples 179) and healthy control (Genotype-Tissue Expression (GTEx) database -number of sample 171) (Figure 2).…”

“…Sphingolipid rheostat, and particularly equilibrium between ceramide and S1P, have been just recently characterized as one of the critical regulator of pro- and anti-apoptotic singling in metabolically dynamic pancreatic cancers. 22,23 Additionally, Speirs et al identified SPHK1 as a key driver of the conserved S1P: Ceramide imbalance in pancreatic cancer subcultures and therefore one of the central controlling hubs of rheostat machinery. 22 The most recent literature data suggested that sphingolipid signaling pathway could be an important novel therapeutic target to suppress proliferation across pancreatic tumors made up of heterogeneous cell populations, with recognition of potential of SPHK1 inhibitors as an approach to reverse healthy balance of pro- and anti-apoptotic signaling in pancreatic cancers.…”

POTEE drives colorectal cancer development via regulating SPHK1/p65 signaling

“…S1P is a bioactive type of sphingolipid, which is converted from ceramide and intracellular S1P was catalyzed mainly by the key sphingosine kinase isoforms, SPHK1 29 . Previous studies have demonstrated that high expression of SPHK1 in tumors was associated with poor prognosis of pulmonary, gastric, pancreatic and colonic cancer patients 30–33 and high expression of phosphorylated SPHK1 could promote cell growth and metastasis 34 . In our work, we consistent expression of SPHK1 with POTEE from both endogenous and exogenous evidence, and they are also positively correlated in the tumor samples of CRC patients.…”