Work

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

Year: 2026

Type: article

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.

Source: Aging Cell

DOI: 10.1111/acel.70477