Egners, A. | Search bioRxiv

bioRxiv2018

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

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.

systems biology↗

bioRxiv2018

Non-canonical HIF-1 stabilization is essential for intestinal tumorigenesis

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of wnt/{beta}-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with nuclear HIF-1 in intestinal adenomas, pointing towards a functional importance of hypoxia-independent, i.e. non-canonical HIF-1 stabilization that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1 stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

cancer biology↗