Právě jsme s @lucieskodova.bsky.social shlédli - skvělé to bylo! 👏 Díky všem, co foukají do balónku 😉 @chmee2.bsky.social

Very cool study, congrats!

A tremendous effort by the first author Lucie Curylova! 👏 Huge thanks to my team @MUNI @FNUSA-ICRC and all collaborators @FNBrno @CEITEC_MUNI. Funded by
#AZVČR (Czech Health Research Council), with institutional support from the National Institute for Cancer Research & the Ministry of Health 🙏

Finally, as all patient-derived models were wild-type p53, our findings suggest that restoring p53 function could offer a promising strategy for treating refractory/metastatic p53-overexpressing pediatric sarcomas, regardless of their TP53 mutational status.

We tested this using paired models with different stemness levels. Our study shows for the first time that reactivating p53 signaling via MDM2/MDMX inhibition selectively induces cell death in aggressive, stem-like Ewing's sarcoma cells while sparing healthy fibroblasts.

Indeed, SOX2 was detected only in human Ewing‘s sarcoma samples that overexpressed p53, indicating disruption of the p53 pathway. Moreover, altered p53 expression was prevalent in metastatic tumors, suggesting p53 as a clinically relevant target for reactivation therapies.

Only cells with high SOX2 or KLF4 expression, along with p53 dysregulation, formed tumors in mice. SOX2 knockdown on a mutant p53 background reduced, but didn’t prevent self-renewal, suggesting p53 dysregulation is crucial for sarcoma cells to acquire a fully stem-like phenotype.

Using a large panel of pediatric sarcoma models, in vivo assays, and tumor tissues, our study provides strong evidence that dysregulated p53 associates with the upregulation of stemness-related transcription factors and enhanced tumorigenicity in pediatric sarcoma cells.

Pediatric sarcomas are bone & soft tissue tumors that often metastasize and show therapy-resistant cancer stem cell traits, making treatment challenging. An impaired p53 pathway is common in aggressive sarcomas, yet its link to sarcoma stemness has been unclear.