Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer

Abstract

Metabolic alterations can serve as targets for diagnosis and therapy of cancer. Due to the highly complex regulation of cellular metabolism, definite identification of metabolic pathway alterations remains challenging and requires sophisticated experimentation. Here, we applied a comprehensive kinetic model of the central carbon metabolism (CCM) to characterize metabolic reprogramming in murine liver cancer. We show that relative differences of protein abundances of metabolic enzymes obtained by mass spectrometry can be used to scale maximal enzyme capacities. Model simulations predicted tumor-specific alterations of various components of the CCM, a selected number of which were subsequently verified by in vitro and in vivo experiments. Furthermore, we demonstrate the ability of the kinetic model to identify metabolic pathways whose inhibition results in selective tumor cell killing. Our systems biology approach establishes that combining cellular experimentation with computer simulations of physiology-based metabolic models enables a comprehensive understanding of deregulated energetics in cancer.

Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment

“…Therefore, we developed a novel approach that combines proteomic analysis of liver tissue with kinetic modeling of liver metabolism. In a preceding work [28], we demonstrated that this approach is capable of correctly predicting the metabolic phenotype of liver tumors in a mouse model. In this work, we used proteomics data on protein abundances in human HCC and the surrounding liver tissue to construct tumor‐specific metabolic models allowing us to monitor a larger panel of metabolites and fluxes in response to a typical plasma profile of metabolites and hormones.…”

Deletion of mTOR in liver epithelial cells enhances hepatic metastasis of colon cancer

“…Cells were used between passages 10 and 25 at approximately 70-90% confluence. Primary murine hepatocytes were isolated from livers of wildtype (WT) and mTOR LEC mice at 8-12 weeks of age and maintained in DMEM with 10% FBS as previously reported [23]. Cells were cultured in a humidified incubator with 5% CO 2 at 37 C.…”