Chromosomal Instability and Centrosome Dynamics: Mechanistic Drivers of Glioblastoma Pathogenesis

Pan-cancer analyses have demonstrated that chromothripsis is unevenly distributed across chromosomes and cancer types. Large-scale whole-genome sequencing studies identified recurrent chromothriptic involvement of specific chromosomes and a high prevalence of chromothripsis in tumors such as glioblastoma. This signifies that chromothripsis is not a random process but may be a chromosome-specific event. Kinetochore size may play a decisive factor for a chromosome to be associated with merotelic attachment. Studies on Indian muntjac fibroblasts demonstrate that chromosomes with larger kinetochores are more susceptible to incorrect merotelic kinetochore–microtubule attachments. Although this specific study was not performed in human cells, a single kinetochore in human cells possesses the capacity to bind with 12–24 microtubules for reliable bi-oriented spindle attachment in the presence of functional proteins responsible for kinetochore-spindle fiber attachment. Hence, in a mechanical context, it is not surprising that a larger kinetochore size likely encourages erroneous kinetochore-spindle attachment during the mitotic cycle.

Upon detecting cytosolic DNA from micronuclei rupture, cGAS synthesizes cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which activates STING, leading to the production of type I interferons and pro-inflammatory cytokines. This activation fosters an anti-tumor immune response by enhancing dendritic cell activation, promoting T cell priming, and augmenting the efficacy of immune checkpoint inhibitors. For further insights into the molecular mechanisms governing cellular homeostasis and autophagy, researchers may refer to the comprehensive reviews on autophagy and signaling pathways . However, in glioblastoma (GBM), epigenetic modifications such as hypermethylation of STING suppress its activity, contributing to immune evasion. The activity of cGAS/STING is also influenced by PTEN expression levels. PTEN mutations in GBM compromise the STING pathway, resulting in a reduction of type I interferon levels and impairing the immune-stimulating system. Hence, it appears that activating the cGAS-STING pathway could potentially convert the “cold” immune microenvironment of glioblastoma into a “hot” tumor, enhancing immunotherapy efficacy. In contrast, chronic activation of cGAS/STING can create an immunosuppressive microenvironment by recruiting Myeloid-Derived Suppressor Cells (MDSCs) and tumor-associated macrophages, dampening effective anti-tumor immunity.

Key Regulatory Factors in Centrosome Cycle and Biogenesis

Supernumerary centrosomes play a significant role in promoting chromosomal instability (CIN) in cancer cells. Cancer cells frequently possess supernumerary centrosomes and depend on centrosome clustering to ensure proper division—a process that contributes to CIN by promoting the formation of merotelic kinetochore attachments. CIN drives alterations in the sequence and copy number of oncogenes, enabling cancer cells to adapt and evolve. Consistent with the importance of these structures, the overexpression of pro-centriolar biogenesis factors, such as Polo-Like Kinase 4 (PLK4), Human Spindle Assembly abnormal protein 6 homolog (HsSAS-6), and Stromal Tumor Infiltrating Lymphocytes (STIL), is directly related to centrosome amplification as reported in different cancer types, including GBM.

Centrosome amplification (CA) is a recurrent cytological hallmark of GBM that converges on a discrete set of regulators whose dysregulation promotes invasion. Core centriole factors such as PLK4 are frequently upregulated in high-grade gliomas and drive centriole overduplication, genomic instability, and pro-invasive phenotypes. Furthermore, Centrosomal protein of 55 KDa (CEP55) is overexpressed in glioma and enhances migration, matrix-remodeling proteases, and stem-like neurosphere formation via the PI3K/AKT–FOXM1 and NF-κB signaling axes. Nevertheless, while supernumerary centrosomes can exist in normal cells, the stabilization of p53 typically exerts cell cycle arrest and induces apoptosis. In contrast, the loss or mutation of p53 disrupts these surveillance mechanisms, allowing cancer cells to cluster centrosomes into pseudo-bipolar spindles. This process enables escape from cell-cycle arrest while increasing chromosome missegregation, thereby fueling the aggressive nature of glioblastoma.