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OS09.5.A UNEXPECTED FUNCTIONAL ROLE OF GLYCOCALYX ENCAPSULATION DURING GBM METABOLIC ADAPTATION OPENS AVENUES FOR NEW TREATMENT CONCEPTS

2024; Oxford University Press; Volume: 26; Issue: Supplement_5 Linguagem: Inglês

10.1093/neuonc/noae144.077

1523-5866

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Kelin Gonçalves de Oliveira, Valeria Governa, Hugo Talbot, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin van Kuppevelt, Karin Forsberg‐Nilsson, Johan Bengzon, Mattias Belting,

Natural Antidiabetic Agents Studies

Abstract BACKGROUND The inherent adaptive capacity of GBM to metabolic stress represents a key clinical challenge, and the underlying mechanisms remain ill-defined. Our lab focuses on the emerging role of lipid metabolism in cancer cell stress adaptation. We have previously found increased scavenging of lipid particles, including extracellular vesicles (EVs) and lipoproteins, during acute stress, further resulting in a lipid droplet (LD) storage phenotype. Here, we propose a new mechanistic link between chondrotin sulfate proteoglycan (CSPG) remodelling, extracellular lipid scavenging, and LD formation that together serve to fine tune intracellular lipid metabolism to escape ferroptosis. MATERIAL AND METHODS We have comprehensively profiled GBM tissues and cells during different acidic stress adaptation conditions, including freshly resected GBM specimens, primary GBM cultures, and established GBM cell-lines. Methods/analyses include: Multiomics (RNA, proteome, glycome), laser capture microdissection for spatial profiling, snRNA-seq, immunophenotyping by FACS and imaging, and in vitro treatment studies (in 2D and 3D) with live imaging of cytotoxicity and ferroptosis. Mouse GBM models were employed for in vivo treatment studies. RESULTS We provide first evidence of a functional role of cell-surface CSPGs during GBM adaptation to metabolic acidosis. Substantial CSPG induction coincides with LD formation in a process dependent on extracellular lipids and acidification. Specifically, CSPG encapsulation of stressed GBM cells acts as a shield against excessive lipid particle scavenging while LDs consitute an intracellular sink for lipid storage. Based on these findings, we introduce combined targeting of CSPGs and LDs as a strategy to challenge the stressed tumor niche. Concomitant disruption of CSPG and LD formation unleashes a metabolic vulnerability in acidic cells driven by uncontrolled lipid uptake and peroxidation, mitochondrial disintegration, and ferroptotic death. CONCLUSION In conclusion, this study identifies a potentially targetable adaptative mechanism in the treatment resistant, acidic niche of GBM. We propose that cancer cell escape from acidic stress involves the induction of CSPGs - providing a shield against the lipid rich tumor microenvironment - and LDs - forming an intracellular lipid sink. Combined targeting of CSPG and LD formation to induce ferroptosis may offer new therapeutic opportunities in GBM and other solid tumors.