The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology

Abstract

Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell-cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cancer stem cells in leukemia and gliomas. Similarly, defining metabolic heterogeneity and fuel-switching signals in nonneoplastic stem cells may also give important insights into the corresponding molecular mechanisms controlling metabolic plasticity in cancer. These advances are important, because metabolic adaptation to anticancer therapeutics is rooted in this inherent metabolic plasticity and is a therapeutic challenge to be overcome.

Figure 1.. Pathways for Fuel Switching in Normal and Neoplastic Brain and Bone Stem Cells.

(A) Low oxygen tension is a physiologic environment in the brain and bone marrow impacting glycolytic metabolism with hypoxia stabilization of HIFs leading to increased expression of genes regulating glycolysis and stem cell maintenance. While tissue culture is typically performed under atmospheric oxygen (21% O₂), lower oxygen levels (1.5-7% O₂) are common in the normal brain and bone marrow with nearly anoxic conditions in portions of solid tumors. All enzymes and/or genes shown in green are induced by hypoxia/HIF with the impact of increasing glycolysis and decreasing oxidative phosphorylation. (B) Perturbation of FOXO3 levels in normal and neoplastic neural (and hematopoietic) stem cells demonstrates a role in the regulation of self-renewal, ROS, and glycolysis due in part to regulation of HIF stability or activity. (C) Normal hematopoietic and neural stem cell signaling indicate the importance of PPARγ transcriptional regulation of CPT1 for fatty acid oxidation. Results in leukemia and brain tumors confirm the importance of fatty acid oxidation as a mechanism for energy production, particularly when glucose levels are low.

Figure 2.. Summary of Metabolic Plasticity in the Context of Stem Cell State and Pathobiology and Potential Therapeutic Interventions.

(A) Tumor environments, importantly oxygen tension as well as nutrient availability, potently impact cellular metabolism which is critical for cell state transitions. Cancer cell activation of developmental programs permits metabolic plasticity critical for adaptations necessary for cell survival. (B) Multiple strategies and specific inhibitors are available to target glycolysis, oxidative phosphorylation, and fatty acid oxidation in cancer cells, but specificity to the tumor is likely to be a concern. By preventing alternative fuel sources and/or maintenance of a quiescent population, combinatorial approaches may sensitize tumor cells to chemo- and radiotherapy.