TY  - JOUR
AU  - Creus-Bachiller, Edgar
AU  - Fernández-Rodríguez, Juana
AU  - Magallón-Lorenz, Miriam
AU  - Ortega-Bertran, Sara
AU  - Navas-Rutete, Susana
AU  - Romagosa, Cleofe
AU  - Silva, Tulio M
AU  - Pané, Maria
AU  - Estival, Anna
AU  - Sidelnikova, Diana Perez
AU  - Morell, Mireia
AU  - Mazuelas, Helena
AU  - Carrió, Meritxell
AU  - Lausová, Tereza
AU  - Reuss, David
AU  - Gel, Bernat
AU  - Villanueva, Alberto
AU  - Serra, Eduard
AU  - Lázaro, Conxi
TI  - Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: new patient-derived orthotopic xenografts, cell lines and tumor entities.
JO  - Molecular oncology
VL  - 18
IS  - 4
SN  - 1574-7891
CY  - Hoboken, NJ
PB  - John Wiley & Sons, Inc.
M1  - DKFZ-2023-02021
SP  - 895-917
PY  - 2024
N1  - 2024 Apr;18(4):895-917
AB  - Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient-derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro-in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another an Neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm, and, finally, an unclassifiable tumor bearing Neurofibromin-2 (NF2) inactivation, an Neuroblastoma RAS Viral Oncogene Homolog (NRAS) oncogenic mutation and a SWI/SNF-related Matrix associated Actin-dependent Regulator of Chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted on treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.
KW  - MPNST (Other)
KW  - NF1 (Other)
KW  - PDOX (Other)
KW  - cellular models (Other)
KW  - treatment response (Other)
KW  - tumor entities (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37798904
DO  - DOI:10.1002/1878-0261.13534
UR  - https://inrepo02.dkfz.de/record/284601
ER  -