2. Academic Validation
  3. Morphofunctional Heterogeneity and Plasticity of Glioblastoma Cells Induced to Senescence by Temozolomide

Morphofunctional Heterogeneity and Plasticity of Glioblastoma Cells Induced to Senescence by Temozolomide

  • Aging Cell. 2026 Apr;25(4):e70477. doi: 10.1111/acel.70477.
Solon Andrades da Rosa 1 2,  Henrique Quaiato de Oliveira 3,  Laura Boose de Mendonça 1 2,  Nicole Borgmann de Oliveira 4,  Mariane da Cunha Jaeger 4,  Luiza Cherobini Pereira 1 2,  Fernanda Dittrich Pinto Oliveira 1 2,  Debora Santos-Sousa 2,  Fernanda Saez-Calazans 2,  Luana Lenz 5,  Melike Lakadamyali 6,  Guido Lenz 1 2,  Eduardo Cremonese Filippi-Chiela 1 2 7 8
Affiliations

Affiliations

  • 1 Programa de Pós-Graduação Em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
  • 2 Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
  • 3 Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
  • 4 Instituto Do Câncer Infantil, Porto Alegre, Rio Grande do Sul, Brazil.
  • 5 Programa de Pós-Graduação Em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil.
  • 6 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 7 Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
  • 8 Departamento de Ciências Morfológicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
PMID: 41963773 DOI: 10.1111/acel.70477
Abstract

Several chemotherapeutics induce Cancer cells to senescence, a persistent growth-arrest state associated with poor Cancer prognosis. Relevant features in cancer Cell Biology, such as phenotypic plasticity and intercellular variability, are poorly understood for senescent cells (SnCs). This study examined the morphofunctional heterogeneity and dynamics of glioblastoma cells induced to senescence by Temozolomide (TMZ), focusing on pro-survival mechanisms, including Autophagy and anti-apoptotic proteins, and phenotypic plasticity. TMZ triggered a proliferative arrest with canonical features of senescence. Two distinct morphotypes emerged with different kinetics: extension-rich (E-state) cells, which were predominant early on, and flattened (F-state) cells, which accumulated over time. These states were interchangeable, mostly from E-state to F-state, as revealed by single-cell tracking. F-state cells exhibited progressive enlargement of cellular and nuclear area, beyond extended survival, suggesting a more stable senescent phenotype despite lower p16 and Autophagy levels than E-state cells. Late Autophagy inhibition using hydroxychloroquine broadly sensitized both morphotypes, reducing enlarged cells. Otherwise, early Autophagy inhibition with 3-methyladenine was not cytotoxic but led to E-state accumulation over F-state cells, suggesting an impact on morphometric dynamics. Beyond Autophagy and p16, F-state cells also expressed lower levels of anti-apoptotic Bcl-2 proteins, indicating differential activation of survival pathways. Notably, the senolytics dasatinib preferentially eliminated E-state cells. These findings highlight the plasticity and heterogeneity of TMZ-induced senescent glioblastoma cells and emphasize the need for selective senotherapeutic strategies aiming to attenuate the pro-tumor effects exerted by SnCs on the tumor microenvironment.

Keywords

autophagy; cellular senescence; heterogeneity; phenotypic plasticity; senolytics.

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