State-of-the-Art Research on Molecular and Cellular Mechanisms of Glioblastoma

Dear Colleagues,

Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor in adults, characterized by rapid progression, inevitable recurrence, and a dismal prognosis despite aggressive multimodal treatment. Beyond its genetic alterations, GBM is defined by extreme cellular and molecular heterogeneity, pervasive genomic instability, and a remarkable capacity for adaptive plasticity. Tumor cells dynamically transition between distinct transcriptional and functional states—including stem-like programs—under the influence of developmental cues, microenvironmental signals, and therapeutic pressure. This plasticity, rather than a rigid cellular hierarchy, underlies the invasive behavior of GBM, its resistance to cytotoxic therapies, and its rapid evolutionary adaptation.

At the tissue level, GBM behaves as a complex and evolving ecosystem, shaped by reciprocal interactions between tumor cells, vascular compartments, immune and glial cells, and the unique constraints of the brain microenvironment. These interactions promote immune evasion, metabolic rewiring, and treatment tolerance, while fueling intra-tumoral diversity. Increasing evidence indicates that therapeutic failure in GBM reflects not only target redundancy, but also the ability of tumor cells to reprogram their identity and exploit vulnerabilities linked to genomic chaos and stress responses.

This Special Issue aims to provide a comprehensive overview of current advances in molecular and cellular GBM research, with a focus on tumor plasticity, evolutionary dynamics, microenvironmental interactions, and emerging therapeutic strategies designed to overcome adaptation and resistance. Contributions bridging fundamental biology and translational perspectives are particularly welcome.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

• Studies addressing the cellular and molecular heterogeneity of glioblastoma, including dynamic transitions between differentiated, stem-like, and therapy-induced cellular states.
• Investigations into the genetic and epigenetic mechanisms driving tumor plasticity, genomic instability, and evolutionary adaptation under therapeutic pressure.
• Research examining chromosomal, mitotic, and genomic instability in glioblastoma, and how controlled or tolerated cellular “chaos” contributes to tumor adaptability, survival, and therapeutic resistance.
• Analyses of glioblastoma cell invasion, migration, and interactions with the brain microenvironment, including vascular, immune, and glial compartments.
• Research exploring the role of developmental and stress-response signaling pathways in shaping tumor cell identity, resistance, and recurrence.
• Studies proposing innovative therapeutic strategies that target tumor adaptability, microenvironmental crosstalk, or vulnerabilities associated with cellular plasticity and genomic instability, alone or in combination with standard treatments.

Prof. Dr. Corinne Auge-Gouillou
Guest Editor

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