We have documented over the past several decades that MYC regulates genes that are involved in glycolysis and glutaminolysis and other central metabolic pathways to achieve cell growth. However, these studies were performed on a timescale that could not detect high frequency fluctuations in metabolite concentrations, which could serve to synchronize interdependent biosynthetic processes to facilitate building of biomass for cell growth and proliferation through their convergence. In preliminary studies, we discovered through 2-hour interval time-series experiments that MYC induction resulted in ultradian (< 24 h periods) oscillations of the concentrations of key intracellular metabolites, such as amino acids, while these nutrients were being depleted from the medium. These observations uncover an intriguing, unsuspected MYC-induced rapid metabolic oscillation (~6 h period) that we hypothesize to be essential for cancer cell growth and proliferation. Moreover, our time-lapse studies of single hypoxic cells using a hypoxia-inducible fluorescent reporter revealed intriguing cycling of hypoxia-inducible factor (HIF) activity with a ~4-5 h period. High extracellular lactate concentrations increased the percentage of hypoxic cells that cycled HIF, suggesting a potential single cell behavior similar to quorum sensing in stressed bacterial populations. These short oscillatory periods are reminiscent of ultradian periods associated with p53-mdm2 activity (6-7 h period), Notch-Hes1 (2 h period), NFkB-IkB signaling (2 h period) and oscillations of glucocorticoid or insulin secretion in vivo. Here we hypothesize that MYC induction of gene expression results in ultradian metabolic oscillations that are essential for cancer cell growth and survival, permitting cells to undergo phases of synchronous nutrient acquisition, respiration, and redox control with convergence of metabolic pathways for biosynthesis. Understanding the mechanistic basis of these metabolic oscillations could lead to new insights into cancer cell survival, revealing new therapeutic strategies. Hence, we set the following Aims:
Aim 1) Determine the role of MYC activation in oscillations of the metabolome.
Aim 2) Determine the role of MYC activation in oscillations of the cistrome, transcriptome, and proteome.
Aim 3) Determine the role of hypoxia in MYC-activated metabolic oscillations.

Public Health Relevance

We have pioneered in discoveries that led to the development of drugs aiming at cutting the cancer cell fuel line. Our recent studies led to a surprising observation that the MYC cancer gene, which plays a significant role in many human cancers, can increase metabolism through pulses of activity, occurring about 4 times a day in cancer cells. This proposal innovates by studying the time component that cancer cells use to grow and survive, enabling an understanding how therapy affects the rapid cycling metabolism of cancer cells and how this oscillation may play a role in treatment responses. Insights from this proposal should yield new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA057341-24A1
Application #
9263109
Study Section
Special Emphasis Panel (ZRG1-OBT-C (02)M)
Program Officer
Spalholz, Barbara A
Project Start
1992-09-01
Project End
2022-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
24
Fiscal Year
2017
Total Cost
$482,205
Indirect Cost
$182,699
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Altman, Brian J; Hsieh, Annie L; Gouw, Arvin M et al. (2017) Correspondence: Oncogenic MYC persistently upregulates the molecular clock component REV-ERB?. Nat Commun 8:14862
Dang, Chi V (2017) Feeding frenzy for cancer cells. Science 358:862-863
Krishnaiah, Saikumari Y; Wu, Gang; Altman, Brian J et al. (2017) Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism. Cell Metab 25:1206
Krishnaiah, Saikumari Y; Wu, Gang; Altman, Brian J et al. (2017) Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism. Cell Metab 25:961-974.e4
Dang, Chi V; Reddy, E Premkumar; Shokat, Kevan M et al. (2017) Drugging the 'undruggable' cancer targets. Nat Rev Cancer 17:502-508
Dang, Chi V (2017) c-MYC mRNA tail tale about glutamine control of transcription. EMBO J 36:1806-1808
Wolpaw, Adam J; Dang, Chi V (2017) Exploiting Metabolic Vulnerabilities of Cancer with Precision and Accuracy. Trends Cell Biol :
Dang, Chi V (2017) MUC-king with HIF May Rewire Pyrimidine Biosynthesis and Curb Gemcitabine Resistance in Pancreatic Cancer. Cancer Cell 32:3-5
Altman, Brian J; Stine, Zachary E; Dang, Chi V (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16:619-34
Yan, Xiaohui; Hu, Zhongyi; Feng, Yi et al. (2015) Comprehensive Genomic Characterization of Long Non-coding RNAs across Human Cancers. Cancer Cell 28:529-540

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