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.

• Keywords
• Cancer stemness, Pediatric sarcomas, Prognosis, Targeted therapy, p53,
• MeSH
• Child MeSH
• Kruppel-Like Factor 4 * MeSH
• Humans MeSH
• Adolescent MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neoplastic Stem Cells * metabolism   pathology   MeSH
• Tumor Suppressor Protein p53 * metabolism   genetics   MeSH
• Child, Preschool MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Sarcoma * genetics   pathology   metabolism   MeSH
• Signal Transduction MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• KLF4 protein, human MeSH Browser
• Klf4 protein, mouse MeSH Browser
• Kruppel-Like Factor 4 * MeSH
• Tumor Suppressor Protein p53 * MeSH