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.

中文翻译：

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脂质代谢的改变标志着胶质母细胞瘤干细胞和非干细胞位于不同的肿瘤微环境中


胶质母细胞瘤（GBM）表现出明显的细胞和代谢异质性，该异质性随肿瘤内细胞微环境的不同而变化。长期以来，代谢靶向一直被提倡作为包括 GBM 在内的许多肿瘤的治疗方法，但如何改变脂质代谢以适应不同的微环境条件以及癌症干细胞 (CSC) 是否改变了脂质代谢是该领域的突出问题。我们利用空间捕获 RNA 测序技术，研究了 GBM 类器官模型的不同微环境中的基因表达，这些模型模拟了营养丰富和营养贫乏的假栅栏/坏死周围肿瘤区域之间的转变。我们揭示了来自同一患者的不同细胞群之间脂质加工基因表达和总脂质含量的显着差异，在缺氧类器官核心以及原发性患者肿瘤的坏死周围和假栅栏区域中脂质富集。这伴随着临床 GBM 标本的类器官核心和假栅栏区域中缺氧诱导的脂滴相关 (HILPDA) 基因表达的区域性上调，但低级别脑肿瘤则不然。在类器官模型和异种移植肿瘤中，与非 CSC 相比，CSC 具有较低的脂滴积累，并且前瞻性分选的低脂 GBM 细胞在功能上富集了干细胞活性。对多个患者来源模型的靶向脂质组学分析揭示了 GBM CSC 和非 CSC 之间脂质代谢的显着变化，表明脂质水平可能不仅仅是微环境的产物，而且可能是细胞状态的反映。 与非 CSC 相比，CSC 的主要类别中性脂质水平降低，但由于脂肪酸去饱和酶 (FADS1/2) 的高表达，多不饱和脂肪酸的产量显着增加，这对于维持 CSC 活力和自我更新至关重要。我们的数据表明，大多数患者临床上存在空间和层次上不同的脂质代谢表型，可以在实验室模型中重现，并且可能代表 GBM 的治疗靶点。