Phenotype-based cell-specific metabolic modeling reveals metabolic liabilities of cancer

Elife. 2014 Nov 21:3:e03641. doi: 10.7554/eLife.03641.

Abstract

Utilizing molecular data to derive functional physiological models tailored for specific cancer cells can facilitate the use of individually tailored therapies. To this end we present an approach termed PRIME for generating cell-specific genome-scale metabolic models (GSMMs) based on molecular and phenotypic data. We build >280 models of normal and cancer cell-lines that successfully predict metabolic phenotypes in an individual manner. We utilize this set of cell-specific models to predict drug targets that selectively inhibit cancerous but not normal cell proliferation. The top predicted target, MLYCD, is experimentally validated and the metabolic effects of MLYCD depletion investigated. Furthermore, we tested cell-specific predicted responses to the inhibition of metabolic enzymes, and successfully inferred the prognosis of cancer patients based on their PRIME-derived individual GSMMs. These results lay a computational basis and a counterpart experimental proof of concept for future personalized metabolic modeling applications, enhancing the search for novel selective anticancer therapies.

Keywords: cancer; cell biology; genome-scale metabolic modeling; human; human biology; medicine; personalized medicine; selective drug targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / metabolism
  • Carboxy-Lyases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Citric Acid Cycle / drug effects
  • Fatty Acids / biosynthesis
  • Gene Knockdown Techniques
  • Genome, Human
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Models, Biological*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Oxidation-Reduction / drug effects
  • Phenotype
  • Precision Medicine

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Fatty Acids
  • Carboxy-Lyases
  • malonyl-CoA decarboxylase