p21-Dependent Senescence Induction by BMP4 Renders Glioblastoma Cells Vulnerable to Senolytics

Glioblastoma (GBM) is a highly malignant brain tumor with extensive cellular heterogeneity and plasticity. Bone morphogenetic protein 4 (BMP4) has shown potential as a therapeutic agent by promoting differentiation, but its effects are complex and context dependent. While BMP4's role in differentiation is well established, its impact on senescence remains unclear. This study investigates BMP4's ability to induce senescence in GBM cells. Primary GBM cultures were treated with BMP4 and analyzed for senescence markers, including cell enlargement, p21 expression, senescence-related gene enrichment, and senescence-associated-β-galactosidase activity. A p21 knockout model was used to determine its role in BMP4-induced senescence, and sensitivity to the senolytic agent navitoclax was evaluated. BMP4 induced senescence in the GBM cultures, particularly in mesenchymal (MES)-like GBM cells with high baseline p21 levels. The knockout of p21 nearly abolished BMP4-induced senescence, maintaining cell size and proliferation. Furthermore, navitoclax effectively eliminated BMP4-induced senescent cells through apoptosis, while sparing cells with normal p21 expression. Our findings highlight BMP4 as an inducer of p21-dependent senescence in GBM, particularly in MES-like cells. This study clarifies BMP4's dual roles in differentiation and senescence, emphasizing their context dependence. Given the strong link between MES-like cells and therapy resistance, their heightened susceptibility to senescence may aid in developing targeted therapies for GBM and potentially other cancers with similar cellular dynamics.