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Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy

Helweg, Laureen P., Storm, Jonathan, Witte, Kaya E., Schulten, Wiebke, Wrachtrup, Lennart, Janotte, Till, Kitke, Angelika, Greiner, Johannes F. W., Knabbe, Cornelius, Kaltschmidt, Barbara, Simon, Matthias, Kaltschmidt, Christian·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms232112919PMC PMC9659205
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Abstract

Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44+/CD133+/Nestin+-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYChigh GSCs being predominantly located in the tumor spheres (“GROW”-state) while NF-κB-RELAhigh GSCs were migrating out of the sphere (“GO”-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM.

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Figures

Figure 1 Isolation and cultivation of primary glioblastoma stem cells (GSCs). (A) Schematic representation of the practical procedure after surgical removal of the tumor. Tissues were sampled, minced, digested, and afterward cultivated under specified selecting/enriching conditions. (B) Exemplary histopathological hematoxylin/eosin staining showed typical cancer cell accumulations within the analyzed GII tumor tissue. Immunostaining of exemplary stained GIV tissue samples for the common cancer stem cell markers (C) CD44 and (D) CD133 depicted specific protein expressions localized in small subgroups of clustered cells. 4′,6-diamidino-2-phenylindol (DAPI) served for nuclear counterstaining. Following differential trypsinization, mesenchymal-shaped cells grew (E) adherently with fetal calf serum and were also able to (F) form spheres without the addition of serum.
Figure 1 Isolation and cultivation of primary glioblastoma stem cells (GSCs). (A) Schematic representation of the practical procedure after surgical removal of the tumor. Tissues were sampled, minced, digested, and afterward cultivated under specified selecting/enriching conditions. (B) Exemplary histopathological hematoxylin/eosin staining showed typical cancer cell accumulations within the analyzed GII tumor tissue. Immunostaining of exemplary stained GIV tissue samples for the common cancer stem cell markers (C) CD44 and (D) CD133 depicted specific protein expressions localized in small subgroups of clustered cells. 4′,6-diamidino-2-phenylindol (DAPI) served for nuclear counterstaining. Following differential trypsinization, mesenchymal-shaped cells grew (E) adherently with fetal calf serum and were also able to (F) form spheres without the addition of serum.CC BY · PubMed Central
Figure 2 Characterization and identification of stemness properties in primary GSCs. Immunocytochemical stainings of the CSC markers CD44 (green) and CD133 (magenta) in GSCs, after (A) adherent growth (exemplary GSC population from donor GII) and in (B) cultured spheres (exemplary (GSC population from donor GV). Presence of Nestin further indicated the stemness character of isolated GSCs, which were also detected via immunocytochemistry of (C) adherent GSCs (exemplary GSC population from donor GII) and after (D) sphere formation (exemplary GSC population from donor GV). DAPI served as nuclear counterstaining. (E) Qualtitative reverse transcriptase polymerase chain reaction (RT-PCR) of MYC, MYCN, OCT4, SOX2, and KLF4 in adherent GSC shows similar expression levels. (F) Quantitative RT-PCR of MYC, MYCN, OCT4, SOX2, and KLF4 in adherent GSCs and spheres reveals similar expression levels in GII and GIV. (G) Flow cytometry of ALDH1 activities in primary GSCs showed respective ALDH1high amounts of 6.06% for GII, 26.00% for GIV, and 3.25% for GV.
Figure 2 Characterization and identification of stemness properties in primary GSCs. Immunocytochemical stainings of the CSC markers CD44 (green) and CD133 (magenta) in GSCs, after (A) adherent growth (exemplary GSC population from donor GII) and in (B) cultured spheres (exemplary (GSC population from donor GV). Presence of Nestin further indicated the stemness character of isolated GSCs, which were also detected via immunocytochemistry of (C) adherent GSCs (exemplary GSC population from donor GII) and after (D) sphere formation (exemplary GSC population from donor GV). DAPI served as nuclear counterstaining. (E) Qualtitative reverse transcriptase polymerase chain reaction (RT-PCR) of MYC, MYCN, OCT4, SOX2, and KLF4 in adherent GSC shows similar expression levels. (F) Quantitative RT-PCR of MYC, MYCN, OCT4, SOX2, and KLF4 in adherent GSCs and spheres reveals similar expression levels in GII and GIV. (G) Flow cytometry of ALDH1 activities in primary GSCs showed respective ALDH1high amounts of 6.06% for GII, 26.00% for GIV, and 3.25% for GV.CC BY · PubMed Central
Figure 3 Tumor necrosis factor α-induced activation of the NF-κB transcription factor in primary GSCs. Confocal analysis revealed (A) expression of NF-κB subunit RELA (exemplary GSC population from donor GII). (B) Quantifying nuclear RELA intensity measured by confocal analysis showed a significant increase of the fold change after stimulation with TNFα for GIV GSCs after 10 min and GV GSCs after 60 min. (C) GCSs express NF-κB subunit c-REL (exemplary GSC population from donor GII). (D) Quantification of nuclear c-REL intensity showed a significant increase of the fold change after stimulation with TNFα for GII GSCs, GIV GSCs as well as GV GSCs after 60 min. Means ± SEM (standard error of the mean) were statistically analyzed by Mann Whitney U tests (n = 5, * p ≤ 0.05, ** p ≤ 0.01).
Figure 3 Tumor necrosis factor α-induced activation of the NF-κB transcription factor in primary GSCs. Confocal analysis revealed (A) expression of NF-κB subunit RELA (exemplary GSC population from donor GII). (B) Quantifying nuclear RELA intensity measured by confocal analysis showed a significant increase of the fold change after stimulation with TNFα for GIV GSCs after 10 min and GV GSCs after 60 min. (C) GCSs express NF-κB subunit c-REL (exemplary GSC population from donor GII). (D) Quantification of nuclear c-REL intensity showed a significant increase of the fold change after stimulation with TNFα for GII GSCs, GIV GSCs as well as GV GSCs after 60 min. Means ± SEM (standard error of the mean) were statistically analyzed by Mann Whitney U tests (n = 5, * p ≤ 0.05, ** p ≤ 0.01).CC BY · PubMed Central
Figure 4 Expression of MYC-family members is present in GSCs but not regulated through NF-κB. (A) Copy number alteration assay reveals a normal copy number of MYC and MYCN in primary GSCs. Immunocytochemical staining revealed robust expression of (B) MYC and N-MYC in adherently growing GSCs (exemplary GSC population from donor GV) as well as (C) MYC in GSC-derived spheres (exemplary GSC population from donor GV). (D) Quantitative mRNA expression analysis showed a higher expression of MYC and Myc-associated factor X (MAX) than MYCN. (E–G) Treatment with TNFα and/or NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) did not significantly change the expression levels of MYCN, MYC, MYCL, and MAX in GSCs.
Figure 4 Expression of MYC-family members is present in GSCs but not regulated through NF-κB. (A) Copy number alteration assay reveals a normal copy number of MYC and MYCN in primary GSCs. Immunocytochemical staining revealed robust expression of (B) MYC and N-MYC in adherently growing GSCs (exemplary GSC population from donor GV) as well as (C) MYC in GSC-derived spheres (exemplary GSC population from donor GV). (D) Quantitative mRNA expression analysis showed a higher expression of MYC and Myc-associated factor X (MAX) than MYCN. (E–G) Treatment with TNFα and/or NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) did not significantly change the expression levels of MYCN, MYC, MYCL, and MAX in GSCs.CC BY · PubMed Central
Figure 5 Migration analysis shows involvement of MYC in cell growth and RELA in the migration of GSCs. (A) Schematic representation of MYC and RELA involvement in cellular growth (GROW) and migration (GO). Deposited spheres show (B) high MYC expression within the sphere as well as (C) high RelA expression in GSCs migrating out of the sphere (white arrows).
Figure 5 Migration analysis shows involvement of MYC in cell growth and RELA in the migration of GSCs. (A) Schematic representation of MYC and RELA involvement in cellular growth (GROW) and migration (GO). Deposited spheres show (B) high MYC expression within the sphere as well as (C) high RelA expression in GSCs migrating out of the sphere (white arrows).CC BY · PubMed Central
Figure 6 High-level reduction of GSC viability via NF-κB and MYC inhibition. Pooled cellular viabilities of GSC populations could be reduced via treatment with (A) 100 µM PDTC, reversing the cytoprotective effect of TNFα. (B) Using 250 µM temozolomide (TMZ) decreased the cell viability of GCSs, while PDTC enhanced the cytotoxic effect. Combination of TMZ with TNFα led to cytoprotective effects. (C) Treatment with 40 µM of the MYC inhibitor KJ-Pyr-9 resulted in significantly decreased cellular viabilities alone or in combination with TNFα, TMZ, and PDTC. (D) Normalized isobolograms show antagonistic actions of KJ-Pyr-9 and PDTC in GII and GIV GSCs. (E) Quantitative RT-PCR revealed a higher expression of CD133, CD44, and Nestin in GII GSCs after treatment and similar expression levels of CD133, CD44, and Nestin in GIV GSCs compared to untreated control. Means ± SEM (standard error of the mean) were statistically analyzed by Mann Whitney U tests (n = 9, * p ≤ 0.05, *** p ≤ 0.001).
Figure 6 High-level reduction of GSC viability via NF-κB and MYC inhibition. Pooled cellular viabilities of GSC populations could be reduced via treatment with (A) 100 µM PDTC, reversing the cytoprotective effect of TNFα. (B) Using 250 µM temozolomide (TMZ) decreased the cell viability of GCSs, while PDTC enhanced the cytotoxic effect. Combination of TMZ with TNFα led to cytoprotective effects. (C) Treatment with 40 µM of the MYC inhibitor KJ-Pyr-9 resulted in significantly decreased cellular viabilities alone or in combination with TNFα, TMZ, and PDTC. (D) Normalized isobolograms show antagonistic actions of KJ-Pyr-9 and PDTC in GII and GIV GSCs. (E) Quantitative RT-PCR revealed a higher expression of CD133, CD44, and Nestin in GII GSCs after treatment and similar expression levels of CD133, CD44, and Nestin in GIV GSCs compared to untreated control. Means ± SEM (standard error of the mean) were statistically analyzed by Mann Whitney U tests (n = 9, * p ≤ 0.05, *** p ≤ 0.001).CC BY · PubMed Central
Figure 7 Bortezomib-mediated inhibition of GSC survival. (A) Treatment of GCSs with Bortezomib in concentrations higher than 2.5 nM inhibited cell survival. (B) Calculating half maximal inhibitory concentration revealed values between 2.85 and 6.69 nM.
Figure 7 Bortezomib-mediated inhibition of GSC survival. (A) Treatment of GCSs with Bortezomib in concentrations higher than 2.5 nM inhibited cell survival. (B) Calculating half maximal inhibitory concentration revealed values between 2.85 and 6.69 nM.CC BY · PubMed Central
Figure 8 Cytotoxicity of cultured human natural killer (NK) cells against GSCs. (A) NK cell population after isolation. Lymphocytes plotted as CD3 vs. CD56 expression. CD56 dim (CD56+) NK cells equaling 88.6% of total cells and CD56 bright (CD56++) NK cells 8.5% of total cells. (B) Human NK cells cultured with 500 U/mL IL2 for 13, 20, and 26 days were co-incubated with GSCs at different ratios for four hours. Depicted is the specific lysis of GSCs as means ± SD (standard deviation). Statistical analysis with one-way ANOVA detected no significant differences between the different GSC populations.
Figure 8 Cytotoxicity of cultured human natural killer (NK) cells against GSCs. (A) NK cell population after isolation. Lymphocytes plotted as CD3 vs. CD56 expression. CD56 dim (CD56+) NK cells equaling 88.6% of total cells and CD56 bright (CD56++) NK cells 8.5% of total cells. (B) Human NK cells cultured with 500 U/mL IL2 for 13, 20, and 26 days were co-incubated with GSCs at different ratios for four hours. Depicted is the specific lysis of GSCs as means ± SD (standard deviation). Statistical analysis with one-way ANOVA detected no significant differences between the different GSC populations.CC BY · PubMed Central
Figure 9 Targeting GSCs for the development of efficient chemo- and immunotherapy. Pharmacologic inhibition of NF-κB by PTDC or inhibition of MYC by KJ-Pyr-9 significantly reduces GSC-viability with no cytoprotective effect of TNFα. As an additional cell-therapeutic strategy, NK cells are capable of killing GSCs.
Figure 9 Targeting GSCs for the development of efficient chemo- and immunotherapy. Pharmacologic inhibition of NF-κB by PTDC or inhibition of MYC by KJ-Pyr-9 significantly reduces GSC-viability with no cytoprotective effect of TNFα. As an additional cell-therapeutic strategy, NK cells are capable of killing GSCs.CC BY · PubMed Central

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Metadata

Authors
Helweg, L. P., Storm, J., Witte, K. E., Schulten, W., Wrachtrup, L., Janotte, T., Kitke, A., Greiner, J. F. W., Knabbe, C., Kaltschmidt, B., Simon, M., & Kaltschmidt, C.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-10-26
Volume
23
Issue
21
Pages
12919
ISSN
1422-0067
DOI
10.3390/ijms232112919
PMC
PMC9659205
Cited by
10
References
5
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • University of Bielefeld
  • Deutsche Forschungsgemeinschaft and the Open Access Publication Fund of Bielefeld University
  • Bethel Foundation, Bielefeld, Germany

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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