Most cited article - PubMed ID 34742870
Noncanonical roles of p53 in cancer stemness and their implications in sarcomas
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