Adaptation to microenvironmental stress in glioblastoma. Mechanistic studies and potential targets.
Cerezo-Magaña, Myriam LU
(2022)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
98(2022:98).
- Abstract
- 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... (More) - 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/340eed00-33b3-4137-96af-75efe1bfbfec
- author
- Cerezo-Magaña, Myriam
LU
- supervisor
- opponent
-
- professor Merry, Catherine L.R., Nottingham
- organization
- publishing date
- 2022
- type
- Thesis
- publication status
- published
- subject
- keywords
- Glioblastoma, Tumor microenvironment, EVs, Proteoglycans, Tumor Surfaceome
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- volume
- 98
- issue
- 2022:98
- edition
- 2022
- pages
- 95 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63717990223?pwd=eFFUVkt0d0xzVFN0UUJ5dUhreisxQT09
- defense date
- 2022-06-16 09:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-259-5
- language
- English
- LU publication?
- yes
- id
- 340eed00-33b3-4137-96af-75efe1bfbfec
- date added to LUP
- 2022-05-24 21:05:20
- date last changed
- 2022-05-31 11:53:14
@phdthesis{340eed00-33b3-4137-96af-75efe1bfbfec,
abstract = {{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.<br/>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.<br/>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.<br/>Altogether, this thesis work contributes to mechanistic understanding of stress adaptation in GBM and presents new avenues for target identification strategies.}},
author = {{Cerezo-Magaña, Myriam}},
isbn = {{978-91-8021-259-5}},
issn = {{1652-8220}},
keywords = {{Glioblastoma; Tumor microenvironment; EVs; Proteoglycans; Tumor Surfaceome}},
language = {{eng}},
number = {{2022:98}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Adaptation to microenvironmental stress in glioblastoma. Mechanistic studies and potential targets.}},
url = {{https://lup.lub.lu.se/search/files/119005523/e_nailing_ex_Myriam.pdf}},
volume = {{98}},
year = {{2022}},
}