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Proc Natl Acad Sci U S A. 2019 Feb 7. pii: 201816391. doi: 10.1073/pnas.1816391116. [Epub ahead of print]

Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways.

Jia D1,2, Lu M3, Jung KH4, Park JH4, Yu L1,5, Onuchic JN6,7,8,9, Kaipparettu BA10,11, Levine H6,7,8,12.

Author information

1
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
2
Systems, Synthetic and Physical Biology Program, Rice University, Houston, TX 77005.
3
The Jackson Laboratory, Bar Harbor, ME 04609.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
5
Applied Physics Program, Rice University, Houston, TX 77005.
6
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; jonuchic@rice.edu kaippare@bcm.edu herbert.levine@rice.edu.
7
Department of Biosciences, Rice University, Houston, TX 77005.
8
Department of Physics and Astronomy, Rice University, Houston, TX 77005.
9
Department of Chemistry, Rice University, Houston, TX 77005.
10
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; jonuchic@rice.edu kaippare@bcm.edu herbert.levine@rice.edu.
11
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030.
12
Department of Bioengineering, Rice University, Houston, TX 77005.

Abstract

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities. Previously, by modeling the gene regulation of cancer metabolism we have reported that cancer cells can acquire a stable hybrid metabolic state in which both glycolysis and OXPHOS can be used. Here, to comprehensively characterize cancer metabolic activity, we establish a theoretical framework by coupling gene regulation with metabolic pathways. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis, respectively, with the activities of three major metabolic pathways: glucose oxidation, glycolysis, and fatty acid oxidation. Our model further characterizes the hybrid metabolic state and a metabolically inactive state where cells have low activity of both glycolysis and OXPHOS. We verify the model prediction using metabolomics and transcriptomics data from paired tumor and adjacent benign tissue samples from a cohort of breast cancer patients and RNA-sequencing data from The Cancer Genome Atlas. We further validate the model prediction by in vitro studies of aggressive triple-negative breast cancer (TNBC) cells. The experimental results confirm that TNBC cells can maintain a hybrid metabolic phenotype and targeting both glycolysis and OXPHOS is necessary to eliminate their metabolic plasticity. In summary, our work serves as a platform to symmetrically study how tuning gene activity modulates metabolic pathway activity, and vice versa.

KEYWORDS:

OXPHOS; TNBC; Warburg; hybrid; metabolic reprogramming

PMID:
30733294
DOI:
10.1073/pnas.1816391116

Conflict of interest statement

The authors declare no conflict of interest.

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