title: Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine.
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.
authors: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Joan
authors: J
authors: Castellsagué
authors: Institut de Medicina Predictiva i Personalitzada del Càncer (IMPPC), Badalona, Barcelona, Spain.
authors: Bernat
authors: B
authors: Gel
authors: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Juana
authors: J
authors: Fernández-Rodríguez
authors: Pathology Service, HUB-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Roger
authors: R
authors: Llatjós
authors: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Ignacio
authors: I
authors: Blanco
authors: Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Program ICO-IDIBELL and CIBER Epidemiología y Salud Pública (CIBERESP), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Yolanda
authors: Y
authors: Benavente
authors: Plastic Surgery Service HUB-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Diana
authors: D
authors: Pérez-Sidelnikova
authors: Medical Oncology Service ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Javier
authors: J
authors: García-Del Muro
authors: Plastic Surgery Service HUB-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Joan Maria
authors: JM
authors: Viñals
authors: Pathology Service, HUB-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: August
authors: A
authors: Vidal
authors: Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors: Rafael
authors: R
authors: Valdés-Mas
authors: Institut de Medicina Predictiva i Personalitzada del Càncer (IMPPC), Badalona, Barcelona, Spain.
authors: Ernest
authors: E
authors: Terribas
authors: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Adriana
authors: A
authors: López-Doriga
authors: Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Miguel Angel
authors: MA
authors: Pujana
authors: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Gabriel
authors: G
authors: Capellá
authors: Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors: Xose S
authors: XS
authors: Puente
authors: Institut de Medicina Predictiva i Personalitzada del Càncer (IMPPC), Badalona, Barcelona, Spain clazaro@iconcologia.net avillanueva@iconcologia.net eserra@imppc.org.
authors: Eduard
authors: E
authors: Serra
authors: Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain clazaro@iconcologia.net avillanueva@iconcologia.net eserra@imppc.org.
authors: Alberto
authors: A
authors: Villanueva
authors: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Translational Research Laboratory ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain clazaro@iconcologia.net avillanueva@iconcologia.net eserra@imppc.org.
authors: Conxi
authors: C
authors: Lázaro
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008819:Mice, Nude; D009442:Neurilemmoma / Q000473:pathology* / Q000628:therapy*; D010361:Patients; D057285:Precision Medicine / Q000379:methods*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
keywords: MPNST; NF1; patient‐derived tumor xenograft; preclinical mouse models; sorafenib