Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells

Simple Summary Patients diagnosed with glioblastoma (GBM) brain tumors typically survive less than two years, despite aggressive therapy with surgery, radiation, and chemotherapy. A major factor underlying this lethality is the ability of GBM tumors to adapt to stress, including the stress of treatment. The role of metabolism in this process remains incompletely understood. We, therefore, explored the connection between cellular phenotype, chemotherapeutic stress, and metabolism in GBM. We found that inducing changes in GBM phenotypes led to alterations in metabolic behavior. Further, during treatment with chemotherapy, GBM cells that became resistant to therapy increased their fatty acid uptake. These therapy-induced alterations in nutrient uptake may underlie therapy resistance and deadly recurrence. Among all cancers, glioblastoma (GBM) remains one of the least treatable. One key factor in this resistance is a subpopulation of tumor cells termed glioma stem cells (GSCs). These cells are highly resistant to current treatment modalities, possess marked self-renewal capacity, and are considered key drivers of tumor recurrence. Further complicating an understanding of GBM, evidence shows that the GSC population is not a pre-ordained and static group of cells but also includes previously differentiated GBM cells that have attained a GSC state secondary to environmental cues. The metabolic behavior of GBM cells undergoing plasticity remains incompletely understood. To that end, we probed the connection between GSCs, environmental cues, and metabolism. Using patient-derived xenograft cells, mouse models, transcriptomics, and metabolic analyses, we found that cell state changes are accompanied by sharp changes in metabolic phenotype. Further, treatment with temozolomide, the current standard of care drug for GBM, altered the metabolism of GBM cells and increased fatty acid uptake both in vitro and in vivo in the plasticity driven GSC population. These results indicate that temozolomide-induced changes in cell state are accompanied by metabolic shifts-a potentially novel target for enhancing the effectiveness of current treatment modalities.