Cancer cachexia is a complex multi-organ syndrome associated with anorexia and severe wasting of adipose tissue and skeletal muscle, contributing to the mortality of many patients. Even under this metabolic mayhem, cancer cells are somewhat protected from starvation and continue to expand. This raises a fundamental question of how cancer cells are protected from metabolic stress during cachexia. Understanding this cancer protective mechanism may lead to novel intervention to kill cancer cells under cachectic conditions, thereby improving patients' health. Particularly, development of cancer interventions rendering cancer cells sensitive to malnutrition observed in cachectic patients should be a valuable therapeutic option. We have evidence to suggest that AMPK, which senses energy stress and promotes metabolic homeostasis, may constitute this cancer protective mechanism. In preliminary results, we found that AMPK deletion from MLL-AF9 induced acute myelogenous leukemia (AML) significantly delayed the onset of AML, depleted leukemia-initiating cells (LICs), and disrupted metabolic homeostasis of AML cells. In contrast, deleting AMPK did not affect normal hematopoiesis, demonstrating that leukemic cells are more dependent on AMPK than normal hematopoietic cells. We further found that AMPK-deficient AML LICs are particularly sensitive to glucose deprivation in vitro. Strikingly, the delayed onset of leukemogenesis by AMPK-deficient AML was further delayed by placing the recipient mice on dietary restriction (DR), indicating that physiological metabolic stress in vivo renders leukemia particularly dependent on AMPK. We thus hypothesized that AMPK is required for LICs to resist metabolic stress, and that combining AMPK inhibition with dietary manipulation will suppress AML by disabling the metabolic stress response of AML. Our long-term goal is to understand how leukemia-initiating cells utilize metabolic regulators to survive malnourished conditions often found in cancer patients.
In aim 1, we will determine how AMPK promotes the metabolic homeostasis of AML cells, by performing metabolic flux analysis and quantifying various metabolites in AML cells.
In aim 2, we will determine how AMPK inhibition and dietary manipulation synergize to suppress leukemogenesis.
In aim 3, we will test our hypothesis that Glut1 is a critical regulator of leukemogenesis controlled by AMPK, by deleting and/or inhibiting Glut1. We will also delete other candidate metabolic enzymes that regulate glucose metabolism and examine their function in leukemogenesis and conferring metabolic stress resistance to AML cells. Upon completion of this proposal, we will have deep understanding of the role of AMPK pathway in maintaining leukemia-initiating cells under metabolic stress. Since AMPK is not required for normal hematopoiesis, AMPK inhibition combined with dietary control shown in our study may offer a novel anti-leukemia therapy that targets leukemia without impairing normal HSCs and hematopoiesis.

Public Health Relevance

Why cancer cells are resistant to malnourished condition in cancer patients with cachexia is a fundamentally important question with significant clinical implication. We recently discovered that a metabolic regulator AMPK is required for leukemogenesis and that AMPK deletion sensitizes leukemia-initiating cells to physiological metabolic stress caused by dietary manipulation, raising the possibility that AMPK confers leukemia-initiating cells resistance to metabolic stress caused by diet. We believe our study will have significant impact in understanding metabolic regulation of leukemia cells, by interrogating the cancer protective mechanism against physiological metabolic stress.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA193235-03
Application #
9245651
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Spalholz, Barbara A
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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