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Cells
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The Pivotal Role of Tumor Stem Cells in Glioblastoma
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The Pivotal Role of Tumor Stem Cells in Glioblastoma

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 8611

Special Issue Editors

Dr. Paola Palumbo

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Guest Editor
Department of Life, Health & Environmental Sciences, University of L’Aquila, Via Pompeo Spennati, Building Rita Levi Montalcini, Coppito, 67100 L’Aquila, Italy
Interests: inflammation; glioma; cancer stem cells; tumor biology; cyclooxygenase-2; nitric oxide synthase 2
Special Issues, Collections and Topics in MDPI journals
Dr. Silvano J. Santini

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Guest Editor
Department of Life, Health & Environmental Sciences, University of L’Aquila, Via Pompeo Spennati, Building “Rita Levi Montalcini”, Coppito, 67100 L’Aquila, Italy
Interests: dicarbonyl stress; oxidative stress; mitochondrial metabolism

Special Issue Information

Dear Colleagues,

We are delighted to announce the launch of a Special Issue of Cells on all aspects related to the theme of “The Pivotal Role of Tumor Stem Cells in Glioblastoma”. We invite you to contribute original research articles or reviews to share your cutting-edge research, insights, and innovation on new mechanistic, functional, cellular, biochemical, or general evidence of cancer stem cells in glioblastoma.

Glioblastoma is one of the most complex, fast-growing, aggressive, and treatment-resistant cancers with an extremely poor prognosis. The latest therapeutic approaches are rarely effective due to the presence of tumor stem cells (TSC) that play a crucial role in resistance and recurrence.

TSCs can also strongly affect the tumor microenvironment, influencing all neighboring resident cell fate by genetic reprogramming and inducing some key stemness features. The precise molecular mechanisms underlying the intricate scenario of TSC are not yet fully understood. A deeper understanding of the TSCs' molecular and biological features could certainly allow us to define new, targeted, and more effective therapeutic approaches to overcome cancer resistance to improve survival rate and treatment response.

We look forward to your contributions.

Dr. Paola Palumbo
Dr. Silvano J. Santini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glioblastoma stem cells
  • resistance
  • cancer therapy
  • signaling pathways
  • tumor microenvironment

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Published Papers (6 papers)

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Research

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18 pages, 3222 KiB  
Article
Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells
by Amanda L. Johnson, Harmon S. Khela, Jack Korleski, Sophie Sall, Yunqing Li, Weiqiang Zhou, Karen Smith-Connor, John Laterra and Hernando Lopez-Bertoni
Cells 2025, 14(8), 592; https://doi.org/10.3390/cells14080592 - 14 Apr 2025
Viewed by 284
Abstract
Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are [...] Read more.
Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2high GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics. Full article
(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)
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19 pages, 3445 KiB  
Article
Microglia-Derived Brain Macrophages Associate with Glioblastoma Stem Cells: A Potential Mechanism for Tumor Progression Revealed by AI-Assisted Analysis
by Yuqi Zheng, Haneya Fuse, Islam Alzoubi and Manuel B. Graeber
Cells 2025, 14(6), 413; https://doi.org/10.3390/cells14060413 - 11 Mar 2025
Viewed by 640
Abstract
Background: Malignant gliomas, and notably glioblastoma, are highly aggressive brain tumors. Understanding the mechanisms underlying their progression is crucial for developing more effective treatments. Recent studies have highlighted the role of microglia and brain macrophages in glioblastoma development, but the specific interactions between [...] Read more.
Background: Malignant gliomas, and notably glioblastoma, are highly aggressive brain tumors. Understanding the mechanisms underlying their progression is crucial for developing more effective treatments. Recent studies have highlighted the role of microglia and brain macrophages in glioblastoma development, but the specific interactions between these immune cells and glioblastoma stem cells (GSCs) remain unclear. Methods: To address this question, we have utilized AI-assisted cell recognition to investigate the spatial relationship between GSCs expressing high levels of CD276 (B7-H3) and microglia- and bone marrow-derived brain macrophages, respectively. Results: Using PathoFusion, our previously developed open-source AI framework, we were able to map specific immunohistochemical phenotypes at the single-cell level within whole-slide images. This approach enabled us to selectively identify Iba1+ and CD163+ macrophages as well as CD276+ GSCs with high specificity and to study their co-localization. Our analysis suggests a closer association of Iba1+ macrophages with GSCs than between CD163+ macrophages and GSCs in glioblastoma. Conclusions: Our findings provide novel insights into the spatial context of tumor immunity in glioblastoma and point to microglia-GSC interactions as a potential mechanism for tumor progression, especially during diffuse tissue infiltration. These findings have significant implications for our understanding of glioblastoma biology, providing a foundation for a comprehensive analysis of microglia activation phenotypes during glioma development. This, in turn, may lead to new therapeutic strategies targeting the early stages of the immune microenvironment of glioblastoma. Full article
(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)
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27 pages, 9280 KiB  
Article
KR158 Spheres Harboring Slow-Cycling Cells Recapitulate High-Grade Glioma Features in an Immunocompetent System
by Avirup Chakraborty, Changlin Yang, Jesse L. Kresak, Aryeh J. Silver, Diana Feier, Guimei Tian, Michael Andrews, Olusegun O. Sobanjo, Ethan D. Hodge, Mia K. Engelbart, Jianping Huang, Jeffrey K. Harrison, Matthew R. Sarkisian, Duane A. Mitchell and Loic P. Deleyrolle
Cells 2024, 13(11), 938; https://doi.org/10.3390/cells13110938 - 29 May 2024
Cited by 1 | Viewed by 1884
Abstract
Glioblastoma (GBM) poses a significant challenge in clinical oncology due to its aggressive nature, heterogeneity, and resistance to therapies. Cancer stem cells (CSCs) play a critical role in GBM, particularly in treatment resistance and tumor relapse, emphasizing the need to comprehend the mechanisms [...] Read more.
Glioblastoma (GBM) poses a significant challenge in clinical oncology due to its aggressive nature, heterogeneity, and resistance to therapies. Cancer stem cells (CSCs) play a critical role in GBM, particularly in treatment resistance and tumor relapse, emphasizing the need to comprehend the mechanisms regulating these cells. Also, their multifaceted contributions to the tumor microenvironment (TME) underline their significance, driven by their unique properties. This study aimed to characterize glioblastoma stem cells (GSCs), specifically slow-cycling cells (SCCs), in an immunocompetent murine GBM model to explore their similarities with their human counterparts. Using the KR158 mouse model, we confirmed that SCCs isolated from this model exhibited key traits and functional properties akin to human SCCs. KR158 murine SCCs, expanded in the gliomasphere assay, demonstrated sphere forming ability, self-renewing capacity, positive tumorigenicity, enhanced stemness and resistance to chemotherapy. Together, our findings validate the KR158 murine model as a framework to investigate GSCs and SCCs in GBM pathology, and explore specifically the SCC–immune system communications, understand their role in disease progression, and evaluate the effect of therapeutic strategies targeting these specific connections. Full article
(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)
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17 pages, 5825 KiB  
Article
Involvement of Cyclooxygenase-2 in Establishing an Immunosuppressive Microenvironment in Tumorspheres Derived from TMZ-Resistant Glioblastoma Cell Lines and Primary Cultures
by Francesca Lombardi, Francesca Rosaria Augello, Serena Artone, Alessia Ciafarone, Skender Topi, Maria Grazia Cifone, Benedetta Cinque and Paola Palumbo
Cells 2024, 13(3), 258; https://doi.org/10.3390/cells13030258 - 30 Jan 2024
Cited by 5 | Viewed by 1961
Abstract
Glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME) strictly associated with therapy resistance. Cyclooxygenase-2 (COX-2) fuels GBM proliferation, stemness, and chemoresistance. We previously reported that COX-2 upregulation induced by temozolomide (TMZ) supported chemoresistance. Also, COX-2 transfer by extracellular vesicles released by [...] Read more.
Glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME) strictly associated with therapy resistance. Cyclooxygenase-2 (COX-2) fuels GBM proliferation, stemness, and chemoresistance. We previously reported that COX-2 upregulation induced by temozolomide (TMZ) supported chemoresistance. Also, COX-2 transfer by extracellular vesicles released by T98G promoted M2 polarization in macrophages, whereas COX-2 inhibition counteracted these effects. Here, we investigated the COX-2 role in the stemness potential and modulation of the GBM immunosuppressive microenvironment. The presence of macrophages U937 within tumorspheres derived from GBM cell lines and primary cultures exposed to celecoxib (COX-2 inhibitor) with or without TMZ was studied by confocal microscopy. M2 polarization was analyzed by TGFβ-1 and CD206 levels. Osteopontin (OPN), a crucial player within the TME by driving the macrophages’ infiltration, and CD44 expression was assessed by Western blot. TMZ strongly enhanced tumorsphere size and induced the M2 polarization of infiltrating macrophages. In macrophage-infiltrated tumorspheres, TMZ upregulated OPN and CD44 expression. These TMZ effects were counteracted by the concurrent addition of CXB. Remarkably, exogenous prostaglandin-E2 restored OPN and CD44, highlighting the COX-2 pivotal role in the protumor macrophages’ state promotion. COX-2 inhibition interfered with TMZ’s ability to induce M2-polarization and counteracted the development of an immunosuppressive TME. Full article
(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)
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16 pages, 3027 KiB  
Article
Prospective Approach to Deciphering the Impact of Intercellular Mitochondrial Transfer from Human Neural Stem Cells and Brain Tumor-Initiating Cells to Neighboring Astrocytes
by Jerusha Boyineni, Jason Michael Wood, Aditya Ravindra, Ethan Boley, Sarah E. Donohue, Marcelo Bento Soares and Sergey Malchenko
Cells 2024, 13(3), 204; https://doi.org/10.3390/cells13030204 - 23 Jan 2024
Cited by 2 | Viewed by 2726
Abstract
The communication between neural stem cells (NSCs) and surrounding astrocytes is essential for the homeostasis of the NSC niche. Intercellular mitochondrial transfer, a unique communication system that utilizes the formation of tunneling nanotubes for targeted mitochondrial transfer between donor and recipient cells, has [...] Read more.
The communication between neural stem cells (NSCs) and surrounding astrocytes is essential for the homeostasis of the NSC niche. Intercellular mitochondrial transfer, a unique communication system that utilizes the formation of tunneling nanotubes for targeted mitochondrial transfer between donor and recipient cells, has recently been identified in a wide range of cell types. Intercellular mitochondrial transfer has also been observed between different types of cancer stem cells (CSCs) and their neighboring cells, including brain CSCs and astrocytes. CSC mitochondrial transfer significantly enhances overall tumor progression by reprogramming neighboring cells. Despite the urgent need to investigate this newly identified phenomenon, mitochondrial transfer in the central nervous system remains largely uncharacterized. In this study, we found evidence of intercellular mitochondrial transfer from human NSCs and from brain CSCs, also known as brain tumor-initiating cells (BTICs), to astrocytes in co-culture experiments. Both NSC and BTIC mitochondria triggered similar transcriptome changes upon transplantation into the recipient astrocytes. In contrast to NSCs, the transplanted mitochondria from BTICs had a significant proliferative effect on the recipient astrocytes. This study forms the basis for mechanistically deciphering the impact of intercellular mitochondrial transfer on recipient astrocytes, which will potentially provide us with new insights into the mechanisms of mitochondrial retrograde signaling. Full article
(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)
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Review

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20 pages, 615 KiB  
Review
Glioblastoma Stem Cells at the Nexus of Tumor Heterogeneity, Immune Evasion, and Therapeutic Resistance
by Justin Tang, Md Al Amin and Jian L. Campian
Cells 2025, 14(8), 562; https://doi.org/10.3390/cells14080562 - 9 Apr 2025
Viewed by 533
Abstract
Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to [...] Read more.
Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches—such as perivascular or hypoxic microenvironments—that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients. Full article
(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)
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