Recently, lipid metabolism has emerged as a potential therapeutic target to treat gliomas, including GBM, and brain metastases. These lipid stores can be used as an energy reservoir, can fuel GBM cell proliferation, and must be maintained to avoid oxidative damage and lipotoxicity. GBM tumors also accumulate more fatty acids than surrounding normal brain tissue. Lipid metabolism is abnormally regulated in gliomas compared to normal cells, with changes in the expression of lipid-related genes such as SREBP1 and FAS, which results in altered lipid composition and lipogenesis to keep up with energy demands. Critically for treatment, this diversity within the cell population means that while cells from one microenvironment or cellular state may respond to a therapy, others may not, resulting in therapeutic resistance of the overall tumor. At the single cell level, GBM is highly heterogeneous with a spectrum of stem cell and metabolic phenotypes, and contains both fast-cycling and slow-cycling cells that have distinct metabolisms and cancerous phenotypes. Maintenance of heterogeneity may be driven by a population of cells within the tumor termed cancer stem cells (CSCs), which are highly plastic and responsive to their environment and hold self-renewal and tumor initiation capacity. A key challenge to GBM treatment is the intratumoral heterogeneity at both the cellular and microenvironmental levels. Despite aggressive standard treatment strategies including surgical resection followed by radiation and chemotherapy, the median survival for patients with GBM is approximately 15В months from the time of diagnosis. Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Our data demonstrate spatially and hierarchically distinct lipid metabolism phenotypes occur clinically in the majority of patients, can be recapitulated in laboratory models, and may represent therapeutic targets for GBM. CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs, but had significantly increased polyunsaturated fatty acid production due to high fatty acid desaturase (FADS1/2) expression which was essential to maintain CSC viability and self-renewal. Targeted lipidomic analysis of multiple patient-derived models revealed a significant shift in lipid metabolism between GBM CSCs and non-CSCs, suggesting that lipid levels may not be simply a product of the microenvironment but also may be a reflection of cellular state. CSCs have low lipid droplet accumulation compared to non-CSCs in organoid models and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. This was accompanied by regionally restricted upregulation of hypoxia-inducible lipid droplet-associated (HILPDA) gene expression in organoid cores and pseudopalisading regions of clinical GBM specimens, but not lower-grade brain tumors. We revealed a striking difference in lipid processing gene expression and total lipid content between diverse cell populations from the same patient, with lipid enrichment in hypoxic organoid cores and also in perinecrotic and pseudopalisading regions of primary patient tumors. We interrogated gene expression in separate microenvironments of GBM organoid models that mimic the transition between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones using spatial-capture RNA-sequencing. Metabolic targeting has long been advocated as a therapy against many tumors including GBM, but how lipid metabolism is altered to suit different microenvironmental conditions and whether cancer stem cells (CSCs) have altered lipid metabolism are outstanding questions in the field. Glioblastoma (GBM) displays marked cellular and metabolic heterogeneity that varies among cellular microenvironments within a tumor.

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