Neradil, J. | bioRxiv Science

bioRxiv2024

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

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 Ewings 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 Ewings 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. HIGHLIGHTSO_LISOX2 and KLF4 are crucial factors in pediatric sarcoma tumorigenesis C_LIO_LIDysregulated p53 pathway predisposes sarcoma cells to acquire stem-like features C_LIO_LIp53 positivity is associated with early metastasis in pediatric sarcoma patients C_LIO_LIRestoring wild-type p53 signaling selectively kills stem-like Ewings sarcoma cells C_LI

cancer biology↗

bioRxiv2023

Inhibiting mitochondrial translation overcomes multidrug resistance in MYC-driven neuroblastoma via OMA1-mediated integrated stress response

High-risk neuroblastoma remains a clinically challenging childhood tumor with a 5-year survival of only 50%. Tumors overexpressing N-MYC or c-MYC oncoproteins define a group of MYC-driven high-risk neuroblastoma with the most dismal outcomes, mainly caused by treatment failure due to the emergence and regrowth of multidrug-resistant cancer cells. Specific mitochondrial processes have been implicated in the maintenance of aggressive stem-like phenotypes in various cancers. We have recently identified a novel mitochondria-mediated mechanism of neuroblastoma multidrug resistance. However, the potential of pharmacological targeting of mitochondria to overcome therapy resistance and stemness in neuroblastoma remains unclear. Here, we show that c-MYC/N-MYC-driven multidrug-resistant neuroblastoma cells are highly vulnerable to cell death induced by the inhibition of mitochondrial translation. In contrast with normal fibroblasts, doxycycline (DOXY)-mediated inhibition of mitochondrial ribosomes efficiently impaired the survival of neuroblastoma cells regardless of their multidrug resistance and stem-like phenotypes. Mechanistically, inhibiting mitochondrial translation induced the mitochondrial stress-activated integrated stress response (ISR) via the OMA1-eIF2 axis, which preceded neuroblastoma cell death. Strikingly, several oncoproteins associated with poor neuroblastoma prognosis, including c-MYC and N-MYC, were markedly downregulated upon ISR activation. Comparing models of various neuroectodermal tumors and normal fibroblasts, we identified high levels of phosphorylated c-MYC and N-MYC (indicating their activity and rapid turnover) as a factor that predetermines susceptibility of neuroblastoma cells to DOXY-induced cell death. Neuroblastoma cells failed to develop significant DOXY resistance over a long-term repeated (pulsed) selection pressure, further demonstrating mitochondrial protein balance as a clinically relevant vulnerability of cancer cells that rely on high MYC activity. Together, our findings provide insight into mitochondrial retrograde regulatory networks in the context of MYC dependence and demonstrate the mitochondrial translation machinery as a promising therapeutic target in multidrug-resistant MYC-driven neuroblastoma.

cancer biology↗