Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast‐cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic ...glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow‐cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose‐deprived conditions. Fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7‐related metabolic pathways is a viable therapeutic strategy.
Synopsis
Transcriptomic and metabolomic profiling of primary brain tumor cells demonstrate that functionally different glioblastoma (GBM) cell subpopulations depend on distinct metabolic pathways for their growth and survival. More invasive slow cycling tumor cells rely on oxidative phosphorylation and lipid metabolism, suggesting targetable candidates for the inhibition of treatment‐resistant tumors.
Patient‐derived GBM cells contain fast‐cycling cells (FCCs) relying on aerobic glycolysis and slow‐cycling cells (SCCs) depending on mitochondrial oxidative phosphorylation in vivo.
SCCs show increased resistance, invasion, and metabolic gene signatures characteristic of recurrent tumors.
SCCs show increased levels of metabolites and components involved in lipid metabolism, storage, and transport.
Block of FABP7‐dependent exogenous fatty acid uptake decreases resistance of SCCs to chemotherapy and glucose deprivation.
Oxidative phosphorylation and lipid metabolism specify distinct energetic set‐up of invasive brain tumor cells.
Glioblastoma, the most frequent primary malignancy of the central nervous system, is almost universally fatal despite aggressive therapies, such as surgical resection, adjuvant radiation and ...chemotherapy, which remain largely palliative. With increasing evidence showing that glioblastoma cancer stem cells play an important role in tumor escape from conventional therapies and disease recurrence, the targeting of cancer stem cells with different therapeutic strategies provides new avenues of research and confidence for better outcomes. We have previously shown that isolating slow-dividing cells from glioblastoma enriches for a population with cancer stem cell properties. Here, we demonstrate that these slow-dividing cancer stem cells are more invasive and more tolerant to chemotherapy than the rest of the tumor population. Surprisingly, slow-proliferating cells are initially more sensitive to radiation damage. We find a significant overlap between the slow-proliferating compartment and expression of the transcription factor ZEB1, which we have recently identified as a master regulator of stemness and chemoresistance in glioblastoma. Consequently, ZEB1-positive cells also exhibit greater radiosensitivity. Slow proliferating, ZEB1-positive cells accumulate genomic aberrations correlated with retention in the G2/M phase of the cell cycle, rendering these cells more sensitive to radiation damage. However, from this specific subpopulation, a fraction of cells that survive irradiation rebound with a proliferative burst that may contribute to recurrence of more aggressive tumors. This distinct effect of radiation on cancer stem cells points to a previously underappreciated heterogeneity within the cancer stem cell compartment and may open up new avenues of studying and targeting specific cancer stem cell sub-populations.
Glioblastoma, the most frequent primary malignancy of the central nervous system, is almost universally fatal despite aggressive therapies, such as surgical resection, adjuvant radiation and ...chemotherapy, which remain largely palliative. With increasing evidence showing that glioblastoma cancer stem cells play an important role in tumor escape from conventional therapies and disease recurrence, the targeting of cancer stem cells with different therapeutic strategies provides new avenues of research and confidence for better outcomes. We have previously shown that isolating slow-dividing cells from glioblastoma enriches for a population with cancer stem cell properties. Here, we demonstrate that these slow-dividing cancer stem cells are more invasive and more tolerant to chemotherapy than the rest of the tumor population. Surprisingly, slow-proliferating cells are initially more sensitive to radiation damage. We find a significant overlap between the slow-proliferating compartment and expression of the transcription factor ZEB1, which we have recently identified as a master regulator of stemness and chemoresistance in glioblastoma. Consequently, ZEB1-positive cells also exhibit greater radiosensitivity. Slow proliferating, ZEB1-positive cells accumulate genomic aberrations correlated with retention in the G2/M phase of the cell cycle, rendering these cells more sensitive to radiation damage. However, from this specific subpopulation, a fraction of cells that survive irradiation rebound with a proliferative burst that may contribute to recurrence of more aggressive tumors. This distinct effect of radiation on cancer stem cells points to a previously underappreciated heterogeneity within the cancer stem cell compartment and may open up new avenues of studying and targeting specific cancer stem cell sub-populations.
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