Glioblastoma (GBM) almost inevitably recurs within 6-12 months after standard temozolomide-radiotherapy (TMZ-RT) treatment, frequently transitioning to aggressive mesenchymal (MES) states through non-genomic transcriptional reprogramming. Mutations in p53/ TP53 are frequent in recurrent GBM, disabling its tumor suppressor transcriptional activity. In contrast, the related p53 family member, TP63 , is rarely mutated in cancers and has been linked with MES maintenance, stemness, and therapy resistance. However, TP63 exhibits context-dependent tumor-suppressive or oncogenic roles, and its relevance to GBM recurrence remains unclear. Paired therapy naïve and post TMZ-RT treated patient-derived GBM cells underwent bulk RNA sequencing and NanoString nCounter transcriptional profiling. Independent validation was performed using GBM datasets from The Cancer Genome Atlas (TCGA) and the Human Protein Atlas. Functional relevance was assessed through TP63 knockdown in patient-derived recurrent GBM cells. TMZ-RT induced therapy resistance and MES transcriptional programs, including upregulation of TP63 , a MES-associated transcription factor. NanoString and TCGA analyses confirmed elevated TP63 expression in therapy-resistant models and recurrent GBM patient tumors, correlating with MES signatures and poor survival. Human Protein Atlas immunohistochemistry further showed that GBM tumors with positive TP63 protein staining also exhibited high levels of MES markers (CD44, S100A1). TP63 silencing in reduced MES-associated gene expression ( CD44, VEGFA, IL6, IL8 ), increased differentiation markers (DCX, OLIG2, TUBB3 ), and impaired stemness through reduced tumorsphere formation, linking TP63 to MES and stem-like states in recurrent GBM. TP63 associates with poor prognosis and MES/stem-like phenotypes in recurrent GBM, highlighting it as a potential biomarker and therapeutic target. • TP63 acts as an oncogene within recurrent glioblastoma • TP63/ TP63 expression correlates with mesenchymal transcripts/markers in glioblastoma • TP63 promotes a stem-cell phenotype in recurrent glioblastoma • TP63-silencing reduces the mesenchymal stem-like phenotype of recurrent glioblastoma
Martell et al. (Fri,) studied this question.