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| Pàgina inicial > Articles > Articles publicats > Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine |
(Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer) (Institut Català d'Oncologia) (Institut Català d'Oncologia) (Institut Català d'Oncologia) (Institut d'Investigació Biomèdica de Bellvitge) (Institut Català d'Oncologia) (Instituto Universitario de Oncología del Principado de Asturias (Oviedo))| Data: | 2015 |
| Resum: | Malignant peripheral nerve sheath tumors (MPNSTs) 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. We present the generation and characterization of five distinct MPNST orthoxenograft models for preclinical testing and personalized medicine. Four of the models are patient-derived tumor xenografts (PDTX), two independent MPNSTs from the same NF1 patient and two from different sporadic patients. The fifth model is an orthoxenograft derived from an NF1-related MPNST cell line. All MPNST orthoxenografts were generated by tumor implantation, or cell line injection, next to the sciatic nerve of nude mice, and were perpetuated by 7-10 mouse-to-mouse passages. The models reliably recapitulate the histopathological properties of their parental primary tumors. They also mimic distal dissemination properties in mice. Human stroma was rapidly lost after MPNST engraftment and replaced by murine stroma, which facilitated genomic tumor characterization. Compatible with an origin in a catastrophic event and subsequent genome stabilization, MPNST contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Mutational frequency and type of somatic point mutations were highly variable among the different MPNSTs modeled, but very consistent when comparing primary tumors with matched orthoxenografts generated. Unsupervised cluster analysis and principal component analysis (PCA) using an MPNST expression signature of ~1,000 genes grouped together all primary tumor-orthoxenograft pairs. Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines. Following standardization and extensive characterization and validation, the orthoxenograft models were used for initial preclinical drug testing. Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth. The development of genomically well-characterized preclinical models for MPNST allowed the evaluation of novel therapeutic strategies for personalized medicine. |
| Ajuts: | Instituto de Salud Carlos III RD06/0020/1051 Instituto de Salud Carlos III RD06/0020/1050 Instituto de Salud Carlos III RD12/0036/0008 Instituto de Salud Carlos III RD12/0036/0031 Instituto de Salud Carlos III PI10/01422 Instituto de Salud Carlos III PI10/0222 Instituto de Salud Carlos III PI11/01609 Instituto de Salud Carlos III PI12/01528 Instituto de Salud Carlos III PI13/00285 Instituto de Salud Carlos III PIE13/00022 Instituto de Salud Carlos III PI13-01339 Ministerio de Ciencia e Innovación SAF2010-21165 Ministerio de Ciencia e Innovación SAF2013-45836-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR283 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR290 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR1465 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | MPNST ; NF1 ; Patient-derived tumor xenograft ; Preclinical mouse models ; Sorafenib |
| Publicat a: | EMBO molecular medicine, Vol. 7, No. 5 (2015) , p. 608-627, ISSN 1757-4676 |
