2024/12/01 by Lucie Curylova, Iva Staniczková Zambo, Jakub Neradil +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Apoptosis #Biology #Cancer #Cancer research #Cancer stem cell #Cancer-related Molecular Pathways #Gene #Genetics #KLF4 #Mdm2 #Medicine #Metastasis #Osteosarcoma #Pathology #Pediatric cancer #Phenotype #Renal and related cancers #Rhabdomyosarcoma #SOX2 #Sarcoma #Sarcoma Diagnosis and Treatment #Stem cell #Transcription factor
paper · doi:10.1007/s13402-024-01020-x
openalex publication_date 2024/12/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
PURPOSE: Pediatric sarcomas are bone and soft tissue tumors that often exhibit high metastatic potential and refractory stem-like phenotypes, resulting in poor outcomes. Aggressive sarcomas frequently harbor a disrupted p53 pathway. However, whether pediatric sarcoma stemness is associated with abrogated p53 function and might be attenuated via p53 reactivation remains unclear. METHODS: We utilized a unique panel of pediatric sarcoma models and tumor tissue cohorts to investigate the correlation between the expression of stemness-related transcription factors, p53 pathway dysregulations, tumorigenicity in vivo, and clinicopathological features. TP53 mutation status was assessed by next-generation sequencing. Major findings were validated via shRNA-mediated silencing and functional assays. The p53 pathway-targeting drugs were used to explore the effects and selectivity of p53 reactivation against sarcoma cells with stem-like traits. RESULTS: We found that highly tumorigenic stem-like sarcoma cells exhibit dysregulated p53, making them vulnerable to drugs that restore wild-type p53 activity. Immunohistochemistry of mouse xenografts and human tumor tissues revealed that p53 dysregulations, together with enhanced expression of the stemness-related transcription factors SOX2 or KLF4, are crucial features in pediatric osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma development. p53 dysregulation appears to be an important step for sarcoma cells to acquire a fully stem-like phenotype, and p53-positive pediatric sarcomas exhibit a high frequency of early metastasis. Importantly, reactivating p53 signaling via MDM2/MDMX inhibition selectively induces apoptosis in aggressive, stem-like Ewing's sarcoma cells while sparing healthy fibroblasts. CONCLUSIONS: Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.