Lucie Curylova, Iva Staniczkova Zambo, Jakub Neradil, Michal Kyr, Nicola Jurackova, Sarka Pavlova, Kristyna Polaskova, Peter Mudry, Jaroslav Sterba, Renata Veselska, Jan Skoda
{"title":"Dysregulation of the p53 pathway provides a therapeutic target in aggressive pediatric sarcomas with stem-like traits.","authors":"Lucie Curylova, Iva Staniczkova Zambo, Jakub Neradil, Michal Kyr, Nicola Jurackova, Sarka Pavlova, Kristyna Polaskova, Peter Mudry, Jaroslav Sterba, Renata Veselska, Jan Skoda","doi":"10.1007/s13402-024-01020-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13402-024-01020-x","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
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.
Cellular OncologyBiochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍:
The Official Journal of the International Society for Cellular Oncology
Focuses on translational research
Addresses the conversion of cell biology to clinical applications
Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions.
A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients.
In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.