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

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

121 Nedladdningar (Pure)

Sammanfattning

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.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Institutionen för kliniska vetenskaper, Lund
Handledare
  • Belting, Mattias, handledare
  • Bengzon, Johan, Biträdande handledare
  • Welinder, Charlotte, Biträdande handledare
Tilldelningsdatum2022 juni 16
UtgivningsortLund
Utgåva2022
Förlag
ISBN (tryckt)978-91-8021-259-5
StatusPublished - 2022

Bibliografisk information

Defence details
Date: 2022-06-16
Time: 09:15
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63717990223?pwd=eFFUVkt0d0xzVFN0UUJ5dUhreisxQT09
External reviewer(s)
Name: Merry, Catherine L.R.
Title: professor
Affiliation: Nottingham

Ämnesklassifikation (UKÄ)

  • Biokemi och molekylärbiologi

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