Unknown,Transcriptomics,Genomics,Proteomics

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Novel dedifferentiated liposarcoma xenograft models reveal PTEN down regulation as a malignant signature and response to PI3K pathway inhibition

ABSTRACT: Liposarcoma is a type of soft tissue sarcoma, exhibiting poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, emphasizing the need to understand this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. Our study demonstrates that all xenografts recapitulate morphologic and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability is directly correlated with disease specific survival of liposarcoma patients. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multi-kinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. One-color arrays: Vehicle vs combination (rapamycin & sorafenib) treatment for 2 separate dedifferentiated liposarcoma xenografts. Two-color arrays: Comparison of patient tumor, several passages of xenograft generated from that tumor, and cells cultured from xenografted tumors.

ORGANISM(S): Homo sapiens

SUBMITTER: Linh Tran

PROVIDER: E-GEOD-42975 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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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Novel dedifferentiated liposarcoma xenograft models reveal PTEN down regulation as a malignant signature and response to PI3K pathway inhibition

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