{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:45:40Z","timestamp":1789469140442,"version":"build-2803163510"},"reference-count":300,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Despite decades of clinical validation, glioblastoma (GBM) treatment remains tethered to a dismal 15-to-16-month survival plateau, heavily thwarted by the ys blood\u2013brain barrier (BBB) and profound cellular heterogeneity. While the 2021 World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5) fundamentally reoriented diagnosis around definitive molecular signatures, such as isocitrate dehydrogenase (IDH)-wildtype status, epidermal growth factor receptor (EGFR) amplification, and +7\/\u221210 chromosomal alterations, the ultimate obstacle to clinical efficacy is the tumor\u2019s intense non-genetic plasticity. Malignant cells reject rigid hierarchies; single-nucleus insights reveal a fluid transcriptomic continuum spanning neurodevelopmental lineages, novel glia-like or neuronal-like states, and highly resilient proneural-mesenchymal (PM) hybrid populations. This intrinsic dynamism is reinforced by functional neuro-gliomal integration into the host brain via electrochemical TM synapses, an immunologically cold niche dominated by secreted phosphoprotein 1 (SPP1+) myeloid cells, and a self-reinforcing hypoxic-angiogenic loop. Under cytotoxic therapy, these networks execute rapid adaptive remodeling, selecting for hypermutator phenotypes and specialized senescence-associated secretory phenotypes (SASP) that dictate aggressive recurrence.<\/jats:p>","DOI":"10.3390\/genes17091120","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:31:57Z","timestamp":1789464717000},"page":"1120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Architects of Aggression: The Molecular Blueprint of Glioma Progression"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2661-6570","authenticated-orcid":false,"given":"David","family":"Aebisher","sequence":"first","affiliation":[{"name":"Department of Photomedicine and Physical Chemistry, Faculty of Medicine, University of Rzesz\u00f3w, 35-310 Resz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5027-017X","authenticated-orcid":false,"given":"Jakub","family":"Tylutki","sequence":"additional","affiliation":[{"name":"English Division Science Club, Faculty of Medicine, University of Rzesz\u00f3w, 35-310 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0658-5471","authenticated-orcid":false,"given":"Angelika","family":"My\u015bliwiec","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and General Chemistry, Faculty of Medicine, University of Rzesz\u00f3w, 35-310 Resz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazarii","family":"Kozak","sequence":"additional","affiliation":[{"name":"English Division Science Club, Faculty of Medicine, University of Rzesz\u00f3w, 35-310 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5557-5464","authenticated-orcid":false,"given":"Dorota","family":"Bartusik-Aebisher","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and General Chemistry, Faculty of Medicine, University of Rzesz\u00f3w, 35-310 Resz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Angom, R.S., Nakka, N.M.R., and Bhattacharya, S. 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