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Adaptation to microenvironmental stress in glioblastoma. Mechanistic studies and potential targets.

Cerezo-Magaña, Myriam (author)
Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumörmikromiljön,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
 (creator_code:org_t)
ISBN 9789180212595
2022
2022
English 95 s.
Series: Lund University, Faculty of Medicine Doctoral Dissertation Series, 1652-8220
  • Doctoral thesis (other academic/artistic)
Abstract Subject headings
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  • Although the overall mortality in cancer is steadily decreasing, major groups of patients still respond poorly to available treatments. The key clinical challenge addressed in the present thesis work relates to the inherent adaptive capacity of glioblastoma (GBM) tumors, resulting in treatment resistance and dismal prognosis. GBM represents the most common and lethal primary CNS tumor in adults. Tumor hypoxia and associated metabolic acidosis are main traits of GBM, and the adaptive responses include aberrant, intracellular lipid accumulation in lipid droplets (LDs), which associate with GBM and other aggressive cancers.Papers I and II show that scavenging of extracellular vesicles (EVs) may contribute to stress adaptation by transforming tumor cells into the LD+ phenotype. On a mechanistic level, hypoxia-induced EV uptake depended on heparan sulfate proteoglycan (HSPG) endocytosis, preferentially via the lipid raft pathway. In Paper II, we studied glioma cell adaptation to chronic acidosis, which triggered a robust induction of chondroitin sulfate (CS) in in vitro models and patient samples. As a functional consequence, lipid particle scavenging was decreased. Hence, CS induction together with LD loading may be a targetable protective mechanism to avoid lipotoxicity. In Paper III, we investigate whether necrosis, a histological hallmark of GBM, is a scavengeable nutrient source for glioma cells. Preliminary results show efficient transfer of protein, DNA and lipids via cell debris. Robust induction of LDs following debris scavenging may dampen the response to irradiation. LD+ cells were hypersensitive to drugs inhibiting LD biosynthesis or utilization, which deserves further exploration.In Paper IV, we developed a methodology for tumor surfaceome mapping (TS-MAP) from intact tumor specimens. Importantly, the TS-MAP method allows to specifically identify the internalizing activity of a given target, an essential feature for cytotoxic drug delivery using antibody-based therapies.Altogether, this thesis work contributes to mechanistic understanding of stress adaptation in GBM and presents new avenues for target identification strategies.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Keyword

Glioblastoma
Tumor microenvironment
EVs
Proteoglycans
Tumor Surfaceome

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dok (subject category)
vet (subject category)

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