Global profiling of SPARC-regulated metabolic pathways in ovarian cancer

We have previously reported the tumor suppressor effect of SPARC in ovarian cancer through inhibiting cancer cell growth and their interactions within the peritoneal milieu. In the present study, we sought to determine the effect of SPARC on metabolic perturbations associated with ovarian cancer using a syngeneic murine ovarian cancer model in SPARC knockout (KO) mice and their wildtype (WT) counterparts. Murine ID8 ovarian cancer cell line were injected intraperitoneally in SPARC KO and WT mice. Matched intraperitoneal tumor tissue, and ascitic fluid were harvested 6 weeks post-injection of ID8 cells and were subjected to global biochemical metabolomic profiling. In tandem, WT and KO tumors were dissected by LCM-microdissected and were subjected to gene expression profiling. Metabolomic profiling of SPARC KO tumors and ascites revealed significantly altered metabolites associated with glucose, energy, amino acid, and lipid metabolism, as well as redox homeostasis. Integrated transcriptome and metabolome analysis of the top significantly upregulated genes and metabolites in the KO compared to WT tumors and ascitic fluid revealed that the major pathways upregulated in absence of SPARC are those involved in: conversion of glucose to acetyl CoA and entry into the citric acid (TCA) cycle, respiratory electron transport and oxidative phosphorylation (SUCLG2; NDUFAB1; ATP5F1; UQCRH; ATP5H; COX5B; NDUFV1; ATP5O; IDH3B/ succinate, fumarate and pyruvate), protein metabolism (EIF5A; PREB; EIF4H; DAD1; STT3A; RPL4; SUMO1; CCT4; CCT2; IGFBP5; HSPA5; EIF3A; EIF4B; RPS19; EIF3E/ mannose; N-acetylneuraminate; N-glycolylneuraminate; glutamate; spermidine), fatty acid beta oxidation (HADH; TPI1; LPL/glycerol), purine nucleotides de novo biosynthesis and salvage (ATP5F1; ATP5H; PAICS; ATP6V1G1/ aspartate; glycine; glutamate; fumarate). Together, these data provide novel insight on the molecular mechanisms of the SPARC-induced metabolic perturbation associated with ovarian cancer that can be translated into diagnostic and prognostic biomarkers of the disease.