Malignant peripheral nerve sheath tumor: models, biology, and translation

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.

Figure 1.. Morphology and histology of MPNST.

A Photo of MPNST on the right flank of an NF1 patient. Also note the cutaneous neurofibroma tumors and café-au-lait macules surrounding the MPNST. B Hematoxylin and eosin stained paraffin section of the tumor in (A). N; necrotic pseudopalisade. White arrowheads mark mitotic cells. C Ki67 and D pH3 mark proliferating cells in the MPNST. Scale bar: 50 μm.

Figure 2.. Key cellular pathways underpinning MPNST development.

Created with BioRender.com.

Figure 3.. Epigenetic regulation in MPNST.

BRD4, Bromodomain-containing Protein 4; EED, Embryonic Ectoderm Development; EZH2, Enhancer of Zeste Homolog 2; PRC2, Polycomb Repressive Complex 2; RBBP4/7, Retinoblastoma Binding Protein 4/7; SUZ12, Suppressor of Zeste 12. Created with BioRender.com.