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Glioblastoma CD105+ cells define a SOX2- cancer stem cell-like subpopulation in the pre-invasive niche

Li, Jiaxin LU ; Ek, Fredrik LU ; Olsson, Roger LU orcid ; Belting, Mattias LU and Bengzon, Johan LU (2022) In Acta Neuropathologica Communications 10. p.1-17
Abstract

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105+) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105+ cells were isolated and assessed for stem-like characteristics. In vitro, CD105+ cells proliferated and enriched in... (More)

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105+) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105+ cells were isolated and assessed for stem-like characteristics. In vitro, CD105+ cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105+ cells were characterized by Nestin+, Vimentin+ and SOX2-, clearly distinguishing them from SOX2+ GCS. GBM CD105+ cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105+ cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105+ cells. Finally, screening for 88 clinical drugs revealed that GBM CD105+ cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105+ cells in order to reshape the tumor microenvironment and block GBM progression.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CD105, Drug screening, Exome sequencing, Glioma stem-like cell, Tumor microenvironment
in
Acta Neuropathologica Communications
volume
10
article number
126
pages
1 - 17
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85136842603
  • pmid:36038950
ISSN
2051-5960
DOI
10.1186/s40478-022-01422-8
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022. The Author(s).
id
3a69c401-1a05-4838-a50e-237fbbd8284e
date added to LUP
2022-10-25 09:24:48
date last changed
2024-08-08 18:32:58
@article{3a69c401-1a05-4838-a50e-237fbbd8284e,
  abstract     = {{<p>Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105+) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105+ cells were isolated and assessed for stem-like characteristics. In vitro, CD105+ cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105+ cells were characterized by Nestin+, Vimentin+ and SOX2-, clearly distinguishing them from SOX2+ GCS. GBM CD105+ cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105+ cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105+ cells. Finally, screening for 88 clinical drugs revealed that GBM CD105+ cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105+ cells in order to reshape the tumor microenvironment and block GBM progression.</p>}},
  author       = {{Li, Jiaxin and Ek, Fredrik and Olsson, Roger and Belting, Mattias and Bengzon, Johan}},
  issn         = {{2051-5960}},
  keywords     = {{CD105; Drug screening; Exome sequencing; Glioma stem-like cell; Tumor microenvironment}},
  language     = {{eng}},
  pages        = {{1--17}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Acta Neuropathologica Communications}},
  title        = {{Glioblastoma CD105<sup>+</sup> cells define a SOX2<sup>-</sup> cancer stem cell-like subpopulation in the pre-invasive niche}},
  url          = {{http://dx.doi.org/10.1186/s40478-022-01422-8}},
  doi          = {{10.1186/s40478-022-01422-8}},
  volume       = {{10}},
  year         = {{2022}},
}