Abstract
Glioblastoma (GBM) displays marked cellular and metabolic heterogeneity that varies among cellular microenvironments within a tumor. 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. 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. 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. 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. 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. 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 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. 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.
Highlights
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults
Cancer stem cell (CSC) are enriched in the perivascular niche of glioblastoma tumors [37]
GBM organoids can be conceptually divided into two zones—an outer cell-dense rim consists of dividing cells in a high-oxygen and high-nutrient environment provided by the nearby media, mimicking the conditions of the tumor perivascular niche, and a hypoxic core with necrotic cells relatively deprived of the nutrient media components, which phenotypically mimics the hypoxic and perinecrotic regions of GBM tumors (Fig. 1A)
Summary
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite aggressive standard treatment strategies including surgical resection followed by radiation and chemotherapy, the median survival for patients with GBM is approximately 15 months from the time of diagnosis [1]. At the single cell level, GBM is highly heterogeneous with a spectrum of stem cell and metabolic phenotypes [6, 7], and contains both fast-cycling and slow-cycling cells that have distinct metabolisms and cancerous phenotypes [8]. 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
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