bioRxiv: Altered lipid metabolism marks glioblastoma stem and non-stem cells in separate tumor niches

Sajina Shakya, Anthony D Gromovsky, James S Hale, Arnon M Knudsen, Briana Prager, Lisa C Wallace, Luiz OF Penalva, Pavlina Ivanova, H Alex Brown, Bjarne W Kristensen, Jeremy N Rich, Justin D Lathia, J Mark Brown, Christopher G Hubert

Background:

Glioblastoma (GBM) is marked by cellular heterogeneity, including metabolic heterogeneity, that varies among cellular microenvironments in the same tumor. Altered cellular metabolism in cancer is well-established, but how lipid metabolism is altered to suit different microenvironmental conditions and cellular states within a tumor remains unexplored.

Methods:

We assessed GBM organoid models that mimic the transition zone between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones and performed spatial RNA-sequencing of cells to interrogate lipid metabolism. Using targeted lipidomic analysis, we assessed differences in acutely enriched cancer stem cells (CSCs) and non-CSCs from multiple patient-derived models to explore the link between the stem cell state and lipid metabolism.

Results:

Spatial analysis revealed a striking difference in lipid content between microenvironments, with lipid enrichment in the hypoxic organoid cores and the 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 in clinical GBM specimens, but not lower-grade brain tumors, that was specifically localized to pseudopalisading regions of patient 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. The targeted lipidomic analysis revealed that CSCs had decreased levels of major classes of neutral lipids …

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