Dysregulation of the p53 pathway provides a therapeutic target in aggressive pediatric sarcomas with stem-like traits
biorxiv(2024)
Abstract
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 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.
HIGHLIGHTS
### Competing Interest Statement
The authors have declared no competing interest.
* CSC
: cancer stem cell
ES
: Ewing’s sarcoma
FFPE
: formalin-fixed paraffin-embedded
IHC
: immunohistochemistry
mut-p53
: mutant p53
NGS
: next-generation sequencing
OS
: osteosarcoma
RMS
: rhabdomyosarcoma
shCtrl
: shRNA control
shSOX2
: shRNA-mediated knockdown of SOX2
SI
: stemness index
TF
: transcription factor
TMA
: tissue microarray
wt-p53
: wild-type p53
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