Glioblastomas rank among the most lethal of cancers with decades of research adding only a few months to the median survival of patients afflicted with these tumors. The limitations in current therapy have many causes, but one contributing force is the presence of complex cellular heterogeneity that phenocopies the normal brain hierarchy. Normal tissue specific stem cells within this hierarchy pose a danger due to their ability to undergo sustained proliferation. In healthy tissues, stem cells reside in specific niches that provide maintenance cues that constrain proliferation, and these same cells differentiate upon exiting the niche. The stem cell microenvironment is associated with regional variation in oxygen, pH, and nutrient availability. Thus, it is almost certain that the metabolic reprogramming that occurs within the context of oncogenesis represents an element of the cancer stem cell niche. As mitochondrial morphology is linked to metabolic capacity and lineage specification, we are investigating the role of mitochondrial dynamics in driving bioenergetic changes that promote cancer stem cell growth and proliferation. In preliminary studies, glioma stem cells were found to exhibit molecular regulation of mitochondrial fission that was distinct from non- stem tumor cells and neuroprogenitors. As targeting mitochondrial dynamics has been linked to neural protection in degenerative disease, we propose that targeting this heterogeneity in mitochondrial dynamics may represent a selective point of vulnerability for glioma stem cells. In the proposed studies, we will investigate the role of mitochondrial fission in sustaining cancer stem cell health and as a therapeutic modality. Collectively, successful completion of the proposed experiments will provide an enhanced model of glioma hierarchy and drive the development of novel clinical therapies.

Public Health Relevance

Glioblastomas are the most common and lethal brain cancer, containing stem-like cells, called brain tumor initiating cells, which are highly resistant to conventional therapies. Regulation of glioma stem cell metabolism is distinct from normal stem cells and differentiated cancer cells, which provides potentially new ways to target these cancer cells. The proposed studies will focus on the regulation of cellular energy factories, called mitochondria, in glioblastoma stem cells and their heterogeneity within tumor microenvironments to develop new therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA208516-03
Application #
9759836
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Espey, Michael G
Project Start
2017-09-01
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Lu, Bin; Kennedy, Bridget; Clinton, Ryan W et al. (2018) Steric interference from intrinsically disordered regions controls dynamin-related protein 1 self-assembly during mitochondrial fission. Sci Rep 8:10879
Tandler, Bernard; Hoppel, Charles L; Mears, Jason A (2018) Morphological Pathways of Mitochondrial Division. Antioxidants (Basel) 7: