Many cancer and stem cells exhibit a metabolic program that is distinct from most terminally differentiated cells, wherein a smaller fraction of the glycolytic product pyruvate is transported into the mitochondria and oxidized. Through a recent collaborative study, the Rutter and Thummel laboratories recently discovered the identity of the transporter, known as the Mitochondrial Pyruvate Carrier (MPC), which mediates mitochondrial pyruvate entry. Having made this breakthrough, we are now in position to test the hypothesis, first proposed about 40 years ago, that loss of the MPC underlies a portion of the decreased mitochondrial pyruvate oxidation observed in cancers. We have generated significant preliminary data in support of this hypothesis for colon cancers, and our data suggests that intestinal stem cells might exhibit the same phenomenon. We propose to employ a multi-system approach, similar to the one that enabled the initial discovery of the MPC, that uses the powerful strengths of intestinal organoid culture, Drosophila melanogaster, and mouse models of cancer and intestinal homeostasis. Utilizing this approach, we intend to test the hypothesis that mitochondrial pyruvate oxidation is necessary and sufficient to maintain appropriate stem cell homeostasis and can play an instructive role in colon oncogenesis. We will do this through three specific aims that define the mechanistic basis for the regulation and function of the MPC in instructing intestinal stem cell fate and the propensity of oncogenesis as well as define the impact of those mechanisms in intact animal models. This information will establish a new framework for understanding how core metabolic pathways can directly impact the initiation and progression of colon tumors.

Public Health Relevance

Our diets and our metabolism have a profound impact on cellular function and systemic health. We will determine how these effects modulate the division of stem cells in the intestine, with a focus on the impact of these effects on colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA228346-02
Application #
9727937
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Espey, Michael G
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112