The landscape of tiered regulation of breast cancer cell metabolism

Rotem Katzir, Ibrahim H. Polat, Michal Harel, Shir Katz, Carles Foguet, Vitaly A. Selivanov, Philippe Sabatier, Marta Cascante, Tamar Geiger*, Eytan Ruppin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Altered metabolism is a hallmark of cancer, but little is still known about its regulation. In this study, we measure transcriptomic, proteomic, phospho-proteomic and fluxomics data in a breast cancer cell-line (MCF7) across three different growth conditions. Integrating these multiomics data within a genome scale human metabolic model in combination with machine learning, we systematically chart the different layers of metabolic regulation in breast cancer cells, predicting which enzymes and pathways are regulated at which level. We distinguish between two types of reactions, directly and indirectly regulated. Directly-regulated reactions include those whose flux is regulated by transcriptomic alterations (~890) or via proteomic or phospho-proteomics alterations (~140) in the enzymes catalyzing them. We term the reactions that currently lack evidence for direct regulation as (putative) indirectly regulated (~930). Many metabolic pathways are predicted to be regulated at different levels, and those may change at different media conditions. Remarkably, we find that the flux of predicted indirectly regulated reactions is strongly coupled to the flux of the predicted directly regulated ones, uncovering a tiered hierarchical organization of breast cancer cell metabolism. Furthermore, the predicted indirectly regulated reactions are predominantly reversible. Taken together, this architecture may facilitate rapid and efficient metabolic reprogramming in response to the varying environmental conditions incurred by the tumor cells. The approach presented lays a conceptual and computational basis for mapping metabolic regulation in additional cancers.

Original languageEnglish
Article number17760
JournalScientific Reports
Issue number1
StatePublished - 1 Dec 2019


FundersFunder number
European Commission METAFLUXITN-264780
I-CORE Centers of Excellence in Gene Regulation in Complex Human Disease41/11
INFECT EU FP7 program
National Institutes of Health
National Institute on AgingK23AG001033
European Commission
National Cancer Institute, Cairo University
Generalitat de Catalunya2017SGR1033
Agència de Gestió d'Ajuts Universitaris i de Recerca
Israel Science Foundation
European Regional Development FundSAF2017-89673-R
Planning and Budgeting Committee of the Council for Higher Education of Israel


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