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PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve tumor

ABSTRACT: Malignant nerve sheath tumors (MPNST) are rare types of malignant soft tissue sarcomas and characterized by high resistance for current chemotherapeutic strategies, including topoisomerase 2a (TOP2A) inhibitor, etoposide. Although the poor therapeutic or severe side effects of etoposide in MPNST patients are demonstrated, novel molecular targets that promote tumor malignancy have not been identified. Previously, we reported that paired related-homeobox 1 (PRRX1) serves as a malignant factor in human osteosarcoma. Here, we found that expression level of PRRX1 in tumor tissues, especially sarcomas, are higher than in normal tissues using database analysis. PRRX1 was expressed in various human sarcoma tissues, and its level increased during malignant progression from schwannoma or neurofibroma to MPNST. High expression of PRRX1 was also associated with poor prognosis of human MPNST patients, and PRRX1 knockdown suppressed proliferation, invasion and tumorigenic potential of human MPNST cell line, HS-PSS. Immunoprecipitation and mass spectrometry analysis revealed that PRRX1 interacts with TOP2A, and human MPNST patients with high expression of TOP2A showed poor prognosis. Interestingly, database analysis revealed that expression level of TOP2A in tumor tissues were positively correlated with PRRX1. TOP2A knockdown in HS-PSS suppressed proliferation, and inhibited the migration induced by PRRX1A overexpression. Overexpression of PRRX1 and TOP2A cooperatively increased migration and expression of tumor-malignancy associated gene sets, including EMT, mTORC1, KRAS and SRC signaling pathways. Inhibition of PRRX1-TOP2A interaction would be a novel tumor-selective therapeutic strategy that has less severe side effects than current chemotherapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214899 | GEO | 2023/05/31

REPOSITORIES: GEO

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Project description:Background: Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. Methods: We generated five patient-derived MPNST orthoxenograft models (three NF1-related and two sporadic) and performed an exhaustive histological and molecular characterization of primary MPNSTs and their corresponding orthoxenografts. Finally, orthoxenografts models were used as an in vivo pre-clinical platform to test several treatment strategies. Results: MPNST orthoxenografts recapitulate the histopathological properties and preserve the genomic and transcriptomic status of their parental primary tumors. Additionally, they mimic distal dissemination properties in mice. Compatible with an origin in a catastrophic event and subsequent stabilization, MPNSTs contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Although preliminary, the results presented here point to clear differences between NF1-associated and sporadic MPNSTs. In accordance, mutation frequency in sporadic MPNSTs was an order of magnitude higher than in NF1-associated MPNSTs and unsupervised cluster analysis and principal component analysis (PCA) using a MPNST signature perfectly divided the samples between NF1 and sporadic MPNST. Finally, different therapeutic approaches tested in the validated orthoxenograft MPNST models, reveal that sorafenib, or in combination with doxorubicin or rapamycin caused a great tumor reduction in all models. Conclusion: The development of a well-characterized and standardized preclinical model for MPNSTs has laid the foundations for evaluating novel therapeutic strategies in the clinical setting. Moreover, results obtained strongly support the clinical evaluation of Sorafenib in this subset of patients. Primary MPNSTs were implanted in the sciatic nerve of nude mices to create orthoxenograft MPNST models. Several orthoxenograft passages were created. The primary tumor (when available) and passages 1 and 4 were selected for gene expression profiling to demonstrate that the orthoxenografts closely resemble their primary tumors and are stable along xenograft passages.

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PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve tumor

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