CBIO-03. A COMPREHENSIVE CHARACTERIZATION OF THE GBM LIPIDOME REVEALS A MOLECULARLY-DEFINED SUB-GROUP WITH HEIGHTENED SENSITIVITY TO FERROPTOSIS

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth. However, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM tumors and model systems. Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Among the most significant differences between the two groups were lipid length and desaturation. As a consequence of this signature, a subset was more sensitive to lipid peroxidation and ferroptosis. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and lipid peroxidation-induced cell death. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.

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CBMT-43. INTEGRATED LIPIDOMIC AND MOLECULAR ANALYSIS REVEALS A SUBSET OF GLIOBLASTOMA VULNERABLE TO FERROPTOSIS

Neuro-Oncology ◽

10.1093/neuonc/noz175.165 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi42-vi42

Author(s):

Danielle Morrow ◽

Nicholas Bayley ◽

Kevin Williams ◽

Hayato Muranaka ◽

Robert Prins ◽

...

Keyword(s):

Fatty Acids ◽

Lipid Metabolism ◽

Metabolic Phenotype ◽

Molecular Signatures ◽

Critical Feature ◽

Molecular Alterations ◽

Lipidomic Analysis ◽

Regulated Cell Death ◽

Novel Association ◽

Therapeutic Opportunity

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth. However, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of a library of molecularly diverse patient-derived GBM cells (n=30). Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Polyunsaturated fatty acids (PUFAs) were among the most significant lipids that distinguished these two groups of GBM tumors. Intriguingly, this lipid metabolic phenotype was associated with heightened sensitivity to ferroptosis – a newly discovered form of regulated cell death. As PUFA oxidation is a critical feature of ferroptosis, our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and ferroptosis. This relationship may present a new therapeutic opportunity to target ferroptosis in a molecularly-defined subset of GBMs.

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CBIO-05. LIPID METABOLIC REPROGRAMMING SENSITIZES A MOLECULARLY-DEFINED SUBSET OF GLIOBLASTOMAS TO FERROPTOSIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.065 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii16-ii16

Author(s):

Danielle Morrow ◽

David Nathanson ◽

Timothy Cloughesy ◽

Robert Prins ◽

Nicholas Bayley ◽

...

Keyword(s):

Lipid Metabolism ◽

Lipid Droplets ◽

Metabolic Reprogramming ◽

Membrane Phospholipids ◽

Molecular Alterations ◽

Lipidomic Analysis ◽

Novel Association ◽

Therapeutic Opportunity ◽

Dependent Cell ◽

Main Components

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth. However, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM samples. Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Triacylglycerides (TAGs) enriched in polyunsaturated fatty acids (PUFAs) were among the most significantly altered lipids between the two groups of GBM tumors. TAGs are the main components of lipid droplets, which sequester PUFA-TAGs away from membrane phospholipids where their peroxidation can lead to ferroptosis – a regulated from of PUFA-peroxidation dependent cell death. Accordingly, the GBM subgroup with a depletion of PUFA TAGs showed heightened sensitivity to ferroptosis. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and ferroptosis. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.

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DDRE-23. A COMPREHENSIVE CHARACTERIZATION OF THE GBM LIPIDOME REVEALS A MOLECULARLY-DEFINED SUB-GROUP WITH HEIGHTENED SENSITIVITY TO LIPID PEROXIDATION INDUCED CELL DEATH

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab024.045 ◽

2021 ◽

Vol 3 (Supplement_1) ◽

pp. i11-i11

Author(s):

Danielle Morrow ◽

Jenna Minami ◽

Nicholas Bayley ◽

Kevin Williams ◽

Steven Bensinger ◽

...

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Lipid Metabolism ◽

Membrane Phospholipids ◽

Molecular Alterations ◽

Tumor Microenvironments ◽

Novel Association ◽

Therapeutic Opportunity

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth and promote survival. However, the full extent to which lipid content is altered across molecularly heterogeneous patient tumors has yet to be fully elucidated. Additionally, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM tumors across tumor microenvironments both in vivo (n=23) and in vitro (n=30). Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Triacylglycerides (TAGs) enriched in polyunsaturated fatty acids (PUFAs) were among the most significantly altered lipids between the two groups of GBM tumors. TAGs are the main components of lipid droplets, which have been shown to sequester PUFAs away from membrane phospholipids where their sensitivity to peroxidation leads to cell death. The GBM subgroup with a depletion of PUFA TAGs showed heightened sensitivity to lipid peroxidation both under basal conditions and in response to pro-oxidant compounds in vitro. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and lipid peroxidation-induced cell death. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.

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