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Neuro-Oncological Advances in Stem Cell Research: A New Era in...
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Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy

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

Deadline for manuscript submissions: 31 August 2026 | Viewed by 15373

Editor

Prof. Dr. Javier S. Castresana

E-Mail Website
Guest Editor
Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain
Interests: glioblastoma genetics and epigenetics; brain tumor stem cells; experimental treatments against glioblastoma cells; resistance to therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last several years, there have been key advances in cell therapy, especially in the application of stem cells. Different approaches have been developed for the treatment of various diseases, including bone marrow transplants in which, after chemotherapy has destroyed hematopoietic cells, the bone marrow is repopulated with stem cells from the same patient. Other cell therapy approaches involve mesenchymal stem cells and iPSCs (induced pluripotent stem cells derived from somatic cells).

Stem cell therapy can be used to treat degenerative diseases, where the goal is to regenerate normal cells. It can also be used to treat cancer through cellular therapy approaches: here, it is necessary to combat tumor cells (firstly, the most undifferentiated cells, i.e., cancer stem cells, as they are responsible for the initiation and maintenance of the tumor, as well as being the most differentiated cells, and secondly, other tumor cells, which are very different at the molecular level). To achieve this, the first priority is, of course, to understand what cancer stem cells really are. Since the research into this concept began, it has been demonstrated that these cells are mutated versions of normal stem cells, progenitor cells, or even cells differentiated from progenitors; the latter two cases can be identified through cell dedifferentiation programs.  Cancer stem cells are more tumorigenic than the non-stem cells that make up part of the tumor (hundreds or thousands of tumor stem cells are enough to produce a tumor in nude mice xenograft experiments, while millions of non-stem tumor cells are needed to achieve the same objective). Furthermore, cancer stem cells can divide symmetrically, creating two cancer stem cells equal to the previous one, and asymmetrically, giving rise to a cancer stem cell and another more differentiated cell (the tumor progenitor cell that, with only symmetrical division, will give rise to the most differentiated tumor cells). There are specific cancer stem cell markers, such as CD133, CD44, ALDH, and nestin, that help in selecting these cells in vitro, with the aid of magnetic beads that carry antibodies against specific tumor antigens. Success in the true isolation of cancer stem cells depends on the specificity of these tumor antigens.

We invite all scientists working in brain tumors to participate in this Special Issue. We welcome original research articles, reviews, and perspective articles on all aspects related to brain tumor biology and therapy, with an emphasis on brain tumor stem cells as therapeutic targets and/or stem cell therapy as a new way to combat these tumors. We will consider different terminology for cancer stem cells: tumor stem cells, cancer stem-like cells, tumor-initiating cells, neurospheres, spheres, BTSCs (brain tumor stem cells), BTICs (brain tumor-initiating cells), and even side population (SP) cells (a small percentage of cells that can extrude Hoechst 33342 out of the cytoplasm through ABC-ATP-binding cassette transporters).

Mesenchymal stem cells, able to deliver drugs or genes to tumor cells and cancer stem cells, will also be covered in this Special Issue, together with the use of iPSC and NK cells against brain tumor stem cells and other stem cell therapy approaches to combat brain tumors. Models such as patient-derived xenografts, organoids, and organ cultures are welcome. Relevant topics include, but are not limited to, the following: the genetic and epigenetic profiles of brain tumor stem cells, cell and molecular signaling, epithelial-to-mesenchymal transition, angiogenesis, migration and invasion, resistance to therapy, and molecular and cellular heterogeneity.

Prof. Dr. Javier S. Castresana
Guest Editor

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 communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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

  • brain tumor genetics and epigenetics
  • brain tumor stem cells
  • stem cell therapy against brain tumors
  • mesenchymal stem cells
  • iPSC
  • resistance to therapy

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Related Special Issues

Published Papers (6 papers)

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Research

Jump to: Review

16 pages, 6686 KB  
Article
Integrated Spatial and Single-Cell Transcriptomics Reveals Poor Prognostic Ligand–Receptor Pairs in Glioblastoma
by Makoto Yoshimoto, Kengo Sugihara, Kazuya Tokumura, Shohei Tsuji and Eiichi Hinoi
Cells 2025, 14(19), 1540; https://doi.org/10.3390/cells14191540 - 1 Oct 2025
Cited by 6 | Viewed by 4764
Abstract
Glioblastoma (GBM) is an aggressive and lethal malignant brain tumor. Cell–cell interactions (CCIs) in the tumor microenvironment, mediated by ligand–receptor (LR) pairs, are known to contribute to its poor prognosis. However, the prognostic influence of CCIs on patients with GBM and the spatial [...] Read more.
Glioblastoma (GBM) is an aggressive and lethal malignant brain tumor. Cell–cell interactions (CCIs) in the tumor microenvironment, mediated by ligand–receptor (LR) pairs, are known to contribute to its poor prognosis. However, the prognostic influence of CCIs on patients with GBM and the spatial expression profiles of such LR pairs within tumor tissues remain incompletely understood. This study aimed to identify prognostic LR pairs in GBM and their intratumoral localization via multitranscriptomic analysis. The CCIs among GBM cells as well as between GBM and niche cells were comprehensively evaluated using 40,958 cells in single-cell RNA sequencing datasets. They were found to form intercellular networks in GBM by specific LR pairs, which were mainly implicated in extracellular matrix (ECM)-related biological processes. Survival analysis revealed that 13 LR pairs related to ECM biological processes contributed to poor prognosis (p < 0.05, and 95% confidence intervals > 1). Notably, our spatial transcriptomic analysis using three independent GBM cohorts revealed that the identified poor prognostic LR pairs were localized in specific regions within GBM tissues. Although the clinical importance of these LR pairs requires further investigation, our findings suggest potential therapeutic targets for GBM. Full article
(This article belongs to the Special Issue Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy)
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23 pages, 1867 KB  
Article
FGFR1 Inhibition by Pemigatinib Enhances Radiosensitivity in Glioblastoma Stem Cells Through S100A4 Downregulation
by Valérie Gouazé-Andersson, Caroline Delmas, Yvan Nicaise, Julien Nicolau, Juan Pablo Cerapio and Elizabeth Cohen-Jonathan Moyal
Cells 2025, 14(18), 1427; https://doi.org/10.3390/cells14181427 - 11 Sep 2025
Cited by 1 | Viewed by 4491
Abstract
Glioblastoma (GBM) is an aggressive and highly heterogeneous tumor that frequently recurs despite surgery followed by radio-chemotherapy and, more recently, TTFields. This recurrence is largely driven by glioblastoma stem cells (GSCs), which are intrinsically resistant to standard therapies. Identifying molecular targets that underlie [...] Read more.
Glioblastoma (GBM) is an aggressive and highly heterogeneous tumor that frequently recurs despite surgery followed by radio-chemotherapy and, more recently, TTFields. This recurrence is largely driven by glioblastoma stem cells (GSCs), which are intrinsically resistant to standard therapies. Identifying molecular targets that underlie this resistance is therefore critical. Here, we investigated whether the inhibition of FGFR1, previously identified as a key mediator of GBM radioresistance, using pemigatinib, a selective FGFR1–3 inhibitor, could enhance GSC radiosensitivity in vitro and in vivo. Pemigatinib treatment inhibited FGFR1 signaling, promoted proteasome-dependent FGFR1 degradation, and reduced the viability, neurosphere formation, and sphere size in GSCs with unmethylated MGMT, a subgroup known for poor response to standard treatments. In MGMT-unmethylated differentiated GBM cell lines, pemigatinib combined with temozolomide further enhanced radiosensitivity. Transcriptomic analysis revealed that pemigatinib treatment led to the downregulation of S100A4, a biomarker associated with mesenchymal transition, angiogenesis, and immune modulation in GBM. Functional studies confirmed that silencing S100A4 significantly improved GSCs’ response to irradiation. In vivo, pemigatinib combined with localized irradiation produced the longest median survival compared to either treatment alone in mice bearing orthotopic GSC-derived tumors, although the difference was not statistically significant. These findings support further clinical investigation to validate these preclinical findings and determine the potential role of FGFR inhibition as part of multimodal GBM therapy. Full article
(This article belongs to the Special Issue Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy)
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Review

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24 pages, 1765 KB  
Review
The Biomechanics of Glioblastoma: Why Glioblastoma Models and Clinical Reality Diverge
by Karina Köpke, Inge S. Zuhorn and Frank A. E. Kruyt
Cells 2026, 15(10), 876; https://doi.org/10.3390/cells15100876 - 12 May 2026
Cited by 1 | Viewed by 732
Abstract
Glioblastomas (GB) are highly aggressive brain tumors with poor patient prognosis and low survival rates. To identify novel therapeutic targets, the tumor microenvironment (TME) is increasingly examined, with a particular focus on biomechanical changes in the extracellular matrix (ECM) that contribute to GB [...] Read more.
Glioblastomas (GB) are highly aggressive brain tumors with poor patient prognosis and low survival rates. To identify novel therapeutic targets, the tumor microenvironment (TME) is increasingly examined, with a particular focus on biomechanical changes in the extracellular matrix (ECM) that contribute to GB aggressiveness. In GB, the ECM stiffens, regulating cell behavior through mechanotransduction. Preclinical in vitro and ex vivo studies generally report increased stiffness in GB relative to healthy brain tissue, whereas clinical in vivo measurements often report decreased stiffness. This review examines potential causes for this discrepancy, highlighting both biological and technical factors. Preclinical measurements are frequently performed using atomic force microscopy (AFM), while clinical stiffness is assessed via magnetic resonance elastography (MRE). Differences in methodology, including sample preparation, measurement modalities, and spatial scale, partly explain divergent stiffness values. Biological factors such as necrosis, edema, and physical confinement by the skull, which are preserved only in vivo, also contribute to these differences. To reconcile these findings, future research should employ physiologically relevant in vitro models that better replicate in vivo GB biomechanics, together with high-throughput and accurate animal models. Integrating these approaches may clarify the biomechanical landscape of GB and result in more effective therapeutic strategies. Full article
(This article belongs to the Special Issue Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy)
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32 pages, 3583 KB  
Review
Microglia Reprogramming in Glioblastoma: Stem Cell-Derived Factors as Emerging Immunomodulators
by Zahra Amiri, Beatrice Federica Tremonti, Alessandro Corsaro, Alessandra Pattarozzi, Adriana Bajetto, Federica Barbieri, Stefano Thellung and Tullio Florio
Cells 2026, 15(9), 840; https://doi.org/10.3390/cells15090840 - 4 May 2026
Viewed by 1328
Abstract
Glioblastoma (GBM) remains one of the most challenging forms of cancer to treat, despite that extensive molecular profiling is now available. Indeed, intratumoral cellular heterogeneity, receptor redundancy, and adaptive resistance through compensatory signaling limit the impact of targeted therapies. Moreover, immunotherapies also underperform: [...] Read more.
Glioblastoma (GBM) remains one of the most challenging forms of cancer to treat, despite that extensive molecular profiling is now available. Indeed, intratumoral cellular heterogeneity, receptor redundancy, and adaptive resistance through compensatory signaling limit the impact of targeted therapies. Moreover, immunotherapies also underperform: checkpoint blockade and vaccine strategies did not obtain consistent benefits in a low mutational burden, poorly immunogenic tumor microenvironment (TME) dominated by immunosuppressive myeloid cells. In this article, we provide evidence that tumor-associated macrophages (TAMs), a form of CNS resident microglia and infiltrating macrophage, derived from bone marrow, adopt a spatially and transcriptionally distinct, non-binary continuum, shaped by tumor-derived signals and niche constraints, allowing glioma cells to resist to immune and pharmaceutical therapeutics. Metabolic rewiring, including hypoxia-linked glycolytic pressure, lactate signaling, and lipid-associated programs, determine immunosuppressive outputs and restrict plasticity, while epigenetic imprinting (DNA methylation, histone modifications, and chromatin regulators) stabilizes these programs and limits access to inflammatory loci. We discuss how stem cell secretome, and extracellular vesicles (EVs) and their cargo may act as tunable autocrine/paracrine inputs that may bias microglial regulatory control. Finally, we highlight major translational confounders, including EV operational definitions, blood–brain barrier (BBB) permeability and regional exposure, inconsistent dosing units, mixed myeloid compartments, and manufacturing dependent variability. Therefore, an exposure-aware framework that integrates product identity, delivery evidence, state-sensitive potency assays, and functional endpoints would be highly desirable. Full article
(This article belongs to the Special Issue Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy)
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25 pages, 3611 KB  
Review
Neuro-Oncological Perspectives on Cancer Stem Cell Biology in Glioblastoma: Implications for Resection, Recurrence, Targeted Therapy, and Other CNS Tumors
by Karen Salmeron-Moreno, Karthik Papisetty, Chris Donghyun Kim, Thomas McCaffery, Rommi Kashlan, John Theodore, Jennifer Minseo Kim, Josephine Buclez, Hithardhi Duggireddy, Justin Maldonado, Hugo Guerrero-Cázares, Gustavo Pradilla and Tomas Garzon-Muvdi
Cells 2026, 15(5), 413; https://doi.org/10.3390/cells15050413 - 27 Feb 2026
Viewed by 1726
Abstract
Cancer stem cells (CSCs) are increasingly recognized as central drivers of tumorigenesis, therapeutic resistance, and recurrence across diverse malignancies. This review synthesizes our current understanding of CSC biology across CNS tumors, with a focus on glioblastoma, where stem-like cells are sustained by specialized [...] Read more.
Cancer stem cells (CSCs) are increasingly recognized as central drivers of tumorigenesis, therapeutic resistance, and recurrence across diverse malignancies. This review synthesizes our current understanding of CSC biology across CNS tumors, with a focus on glioblastoma, where stem-like cells are sustained by specialized and overlapping tumor microenvironmental niches. Perivascular, hypoxic, invasive, immunosuppressive, and extracellular matrix-associated niches cooperatively enforce stemness, metabolic adaptability, immune evasion, and phenotypic plasticity, enabling CSC persistence despite maximal surgical resection and standard-of-care therapy. Notably, CSCs extend beyond radiographically defined tumor margins and populate peritumoral regions, providing a biological basis for near-universal recurrence. Advances in multiparametric imaging, stem cell-based ex vivo and in vivo models, and single-cell and spatial profiling have refined insight into CSC heterogeneity, niche dependence, and treatment resistance. Together, these findings reframe therapeutic strategies, highlighting the need for function-preserving maximal resection and multimodal therapies that target both CSC-intrinsic pathways and their supportive microenvironments. Full article
(This article belongs to the Special Issue Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy)
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21 pages, 926 KB  
Review
GSCs in the Transdifferentiation Phenomenon: Focus on CAR-T-Based Therapy
by Martina Di Marco, Alessandro Lo Giudice, Francesca Chiara Cecala, Sabrina David, Celeste Caruso Bavisotto, Claudia Campanella, Alessandra Maria Vitale and Giuseppa D’Amico
Cells 2026, 15(4), 363; https://doi.org/10.3390/cells15040363 - 18 Feb 2026
Viewed by 1192
Abstract
Glioblastoma (GBM) remains one of the most lethal brain tumors, largely due to the resilience and plasticity of glioblastoma stem cells (GSCs), which drive tumor growth, recurrence, and resistance to conventional therapies. A key mechanism underlying their aggressiveness is transdifferentiation, whereby GSCs acquire [...] Read more.
Glioblastoma (GBM) remains one of the most lethal brain tumors, largely due to the resilience and plasticity of glioblastoma stem cells (GSCs), which drive tumor growth, recurrence, and resistance to conventional therapies. A key mechanism underlying their aggressiveness is transdifferentiation, whereby GSCs acquire endothelial- and pericyte-like phenotypes, promoting neovascularization and remodeling the tumor microenvironment to sustain malignancy. Conventional treatments often fail to eliminate these resilient populations, highlighting the need for innovative targeted strategies. Chimeric antigen receptor (CAR)-based immunotherapies offer a targeted strategy to specifically eliminate GSCs and interfere with their role in promoting tumor vascularization and suppressing immune responses. This review aims to provide a comprehensive overview of the molecular mechanisms driving GSC transdifferentiation and to summarize the current landscape of CAR-T therapies developed to target these cells. By integrating knowledge of GSC biology with advances in CAR-T-based interventions, this work highlights the potential of next-generation immunotherapies to overcome therapeutic resistance, limit tumor recurrence, and improve clinical outcomes in GBM. Full article
(This article belongs to the Special Issue Neuro-Oncological Advances in Stem Cell Research: A New Era in Brain Tumor Therapy)
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