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Title: Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine
Author: Castellsagué, Joan
Gel, Bernat
Fernández Rodríguez, Juana
Llatjós, Roger
Blanco Guillermo, Ignacio
Benavente, Yolanda
Pérez Sidelnikova, Diana
García del Muro Solans, Xavier
Viñals, Joan Maria
Vidal-Bel, August
Valdés Mas, Rafael
Terribas Pérez, Ernest
López Dóriga Guerra, Adriana
Pujana Genestar, M. Ángel
Capellá, G. (Gabriel)
Puente, Xose S.
Serra Arenas, Eduard
Villanueva Garatachea, Alberto
Lázaro García, Conxi
Keywords: Càncer
Medicina personalitzada
Personalized medicine
Issue Date: 25-Mar-2015
Publisher: EMBO Press
Abstract: 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.
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It is part of: EMBO Molecular Medicine, 2015, vol. 7, num. 5, p. 608-627
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ISSN: 1757-4676
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)

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