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

Acta Neuropathologica Communications

Anthony D. Gromovsky¹  James S. Hale²  J. Mark Brown³  Justin D. Lathia³  Luiz O. F. Penalva⁴  Briana Prager⁵  Sajina Shakya⁶  Lisa C. Wallace⁶  Christopher G. Hubert⁷  Jeremy N. Rich⁸  Arnon M. Knudsen⁹  Bjarne W. Kristensen⁹  H. Alex Brown^1,10 

[1] Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA;Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA;Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA;Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA;Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA;Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA;Children’s Cancer Research Institute, University of Texas Health Sciences Center San Antonio, San Antonio, TX, USA;Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA;Medical Scientist Training Program, Case Western Reserve School of Medicine, Cleveland, OH, USA;Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, ND2-4044195, Cleveland, OH, USA;Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, ND2-4044195, Cleveland, OH, USA;Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA;Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA;Department of Medicine, University of Pittsburgh, Pittsburg, PA, USA;Department of Pathology, Odense University Hospital, Odense, Denmark;Department of Clinical Research, University of Southern Denmark, Odense, Denmark;Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA;

关键词: Glioblastoma;    Organoid;    Tumor heterogeneity;    Lipid droplets;    Cancer stem cell;   

DOI  :  10.1186/s40478-021-01205-7

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY