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Author Spotlight: Finding New Therapeutic Targets for Malignant Peripheral Nerve Sheath Tumor Through Genome-Scale shRNA Screens
Published on: August 25, 2023
Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct
Suganth Suppiah1,2, Sheila Mansouri1, Yasin Mamatjan1,3
1MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, ON, Canada.
Abstract:
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials.
Insights
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, and this study identified two distinct molecular subgroups. Targeting the SHH pathway in one subgroup showed promise in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited treatment options.
- MPNSTs are frequently associated with neurofibromatosis type 1.
Purpose of the Study:
- To identify novel therapeutic targets for MPNST by analyzing molecular profiles.
- To characterize the distinct molecular subgroups within MPNSTs.
Main Methods:
- Multiplatform integrated molecular analysis of 108 peripheral nerve sheath tumors.
- Unsupervised methylome and transcriptome profiling.
- Single nuclei RNA sequencing.
Main Results:
- Two distinct MPNST subgroups identified: MPNST-G1 with SHH pathway activation and MPNST-G2 with WNT/ß-catenin/CCND1 pathway activation.
- Malignant cells in MPNST-G1 exhibit neural crest-like characteristics, while MPNST-G2 cells resemble Schwann cell precursors.
- Inhibition of the SHH pathway suppressed tumor growth and malignant progression in preclinical MPNST models.
Conclusions:
- MPNSTs comprise distinct molecular subtypes with targetable oncogenic programs.
- SHH pathway inhibition is a promising therapeutic strategy for MPNST-G1.
- Further clinical investigation of SHH pathway inhibitors for MPNST is warranted.
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