Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Deciphering cellular and molecular signatures of malignant progression in Neurofibromatosis type 1 using single-cell transcriptomic analysis

ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with currently no effective treatment. While half of MPNSTs arise sporadically, the others are due to the malignant progression of neurofibromas (NFs) in patients with neurofibromatosis type 1 (NF1). NFs are benign nerve sheath tumors due to bi-allelic loss of NF1, encoding a negative regulator of Ras pathway, in the Schwann cell (SC) lineage. We have conceived an Nf1-KO mouse model in which NFs spontaneously transform into MPNSTs To decipher the step-by-step evolution of the cellular composition and biological activities of tumor cells and their microenvironment during the transformation process, we performed single-cell transcriptomic profiling of pNFs, dyNFs and MPNSTs, all issued from Prss56Cre, Nf1fl/fl cohort, using 10x Chromium platform. We discovered that malignant transformation is initiated by a molecular transition of tumor SCs from glial to mesenchymal identity (GMT).

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Fanny Coulpier

PROVIDER: E-MTAB-14222 | 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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Deciphering cellular and molecular signatures of malignant progression in Neurofibromatosis type 1 using single-cell transcriptomic analysis

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