This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-CA-112: Cancer Cell Energy Metabolism and Cancer Causation The molecular events that covert normal cells into tumor cells alter cellular metabolism to aerobic glycolysis, which favors macromolecular synthesis at the expense of efficient ATP production. This metabolic switch that facilitates tumor growth remains a fundamental distinction between normal and tumor cells that has yet to be effectively exploited of cancer therapy. Deregulated tumor cell growth and altered metabolism are also a source of metabolic stress. Oxygen, nutrient and factor deprivation caused by growth to high density and insufficient angiogenesis, and lactate production from glycolysis, are common features and sources of stress in the tumor microenvironment. How tumor and associated stromal cells respond to this stress effects tumor progression and treatment response. Possible responses include cell death (apoptosis or necrosis), cell cycle exit (quiescence or senescence) or adaptation and survival (autophagy). The catabolic process of autophagy is a lysosomal degradation pathway induced by metabolic stress that confers stress tolerance by maintaining energy homeostasis through cellular self-consumption and recycling, and by mitigating oxidative damage through the degradation of malfunctioning organelles and proteins. Autophagy may be particularly important to cells in a glycolytic state and under conditions of metabolic stress. Thus, the adaptation of tumor and associated stromal cells to metabolic stress is intimately linked to their inherent metabolic activity, but the role of metabolism in the context of tumor-stromal interaction is not known. Moreover, exactly how autophagy contributes to cellular metabolism and survival in the tumor microenvironment is not clear. We hypothesize that metabolic adaptation in tumor tissue allows prolonged survival to stress permitting tumor relapse and that discerning the underlying mechanisms will provide new approaches to cancer therapy. To test this hypothesis, we plan to define tumor and stromal cell metabolism, the role of catabolism through autophagy, and the mechanism of metabolic stress adaptation. Growth to high density induces fibroblasts to alter metabolism, activate autophagy, exit the cell cycle, and enter quiescence. We discovered that induction of quiescence of stromal fibroblasts dramatically alters gene expression, including activation of Notch signaling that is required for cell cycle reentry. Remarkably, glucose consumption and utilization is high in quiescent fibroblasts, which causes lactate secretion which can alter the microenvironment;but how does it influence tumorigenesis is not known. Analogous to quiescence in fibroblasts, apoptosis-defective tumor cells subjected to metabolic stress activate autophagy, exit the cell cycle and enter a state of prolonged dormancy from which they can reenter the cell cycle when growth conditions are favorable. We discovered that tumor cell dormancy dramatically alters the cellular proteome and gene expression with evidence of compensatory nutrient uptake, Foxo and Notch pathway activation, and induction of uncharacterized mammalian homologues of yeast genes required for quiescence induced by carbon source limitation. These findings suggest that major metabolic reprogramming accompanies the transition from proliferation to dormancy to cell cycle reentry. These striking parallels between quiescence and dormancy suggest that they are governed by common metabolic reprogramming events that may be a fundamental aspect of tumor biology that has yet to be explored. We propose to define the metabolic networks and role of metabolism as cells transition from proliferation to dormancy or quiescence to cell cycle reentry and how this alters tumor-stromal interaction. Preventing tumor cells from successful metabolic adaptation to stress enabling sustained dormancy and recovery may provide a novel approach to cancer therapy. Cancer cells acquire mutations that deregulate cell growth that also alter cellular metabolism. It has recently become apparent that the metabolic reprogramming of tumor cells is necessary to provide the building blocks for the macromolecular synthesis of proteins, lipids and nucleic acids necessary to support tumor cell growth. Importantly, these metabolic alterations distinguish tumor cells from normal cells, providing a potential therapeutic window and novel targets for anti-cancer drug discovery.

Public Health Relevance

Cancer cells acquire mutations that deregulate cell growth that also alter cellular metabolism. It has recently become apparent that the metabolic reprogramming of tumor cells is necessary to provide the building blocks for the macromolecular synthesis of proteins, lipids and nucleic acids necessary to support tumor cell growth. Importantly, these metabolic alterations distinguish tumor cells from normal cells, providing a potential therapeutic window and novel targets for anti-cancer drug discovery.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
5RC1CA147961-02
Application #
7942941
Study Section
Special Emphasis Panel (ZRG1-OTC-K (58))
Program Officer
Mohla, Suresh
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$500,000
Indirect Cost
Name
Rutgers University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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