Dysregulation of the p53 pathway provides a therapeutic target in aggressive pediatric sarcomas with stem-like traits

Abstract

ABSTRACTPediatric 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 sarcoma stemness is associated with abrogated p53 function and might be attenuated via p53 reactivation remains unclear. Here, we show 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, p53 signaling reactivation via MDM2/MDMX inhibition selectively induces apoptosis in aggressive stem-like Ewing’s sarcoma cells while sparing healthy fibroblasts. Collectively, our results suggest that restoration of canonical p53 activity provides a promising strategy for improving the treatment of pediatric sarcomas with unfavorable stem-like traits.HIGHLIGHTSSOX2 and KLF4 are crucial factors in pediatric sarcoma tumorigenesisDysregulated p53 pathway predisposes sarcoma cells to acquire stem-like featuresp53 positivity is associated with early metastasis in pediatric sarcoma patientsRestoring wild-type p53 signaling selectively kills stem-like Ewing’s sarcoma cells