Related Experiment Video
Updated: Aug 28, 2025
Author Spotlight: Finding New Therapeutic Targets for Malignant Peripheral Nerve Sheath Tumor Through Genome-Scale shRNA Screens
Published on: August 25, 2023
Single-cell sequencing reveals activation of core transcription factors in PRC2-deficient malignant peripheral nerve
Xiyuan Zhang1, Hannah E Lou1, Vishaka Gopalan2
1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Loss-of-function mutations in the polycomb repressive complex 2 (PRC2) occur frequently in malignant peripheral nerve sheath tumor, an aggressive sarcoma that arises from NF1-deficient Schwann cells. To define the oncogenic mechanisms underlying PRC2 loss, we use engineered cells that dynamically reassemble a competent PRC2 coupled with single-cell sequencing from clinical samples. We discover a two-pronged oncogenic process: first, PRC2 loss leads to remodeling of the bivalent chromatin and enhancer landscape, causing the upregulation of developmentally regulated transcription factors that enforce a transcriptional circuit serving as the cell's core vulnerability. Second, PRC2 loss reduces type I interferon signaling and antigen presentation as downstream consequences of hyperactivated Ras and its cross talk with STAT/IRF transcription factors. Mapping of the transcriptional program of these PRC2-deficient tumor cells onto a constructed developmental trajectory of normal Schwann cells reveals that changes induced by PRC2 loss enforce a cellular profile characteristic of a primitive mesenchymal neural crest stem cell.
Insights
Loss of polycomb repressive complex 2 (PRC2) in malignant peripheral nerve sheath tumors causes chromatin changes and reduces immune signaling. This drives tumor growth by reverting cells to a primitive stem cell-like state.
Area of Science:
- Oncology
- Epigenetics
- Cancer Genomics
Background:
- Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma.
- Loss-of-function mutations in polycomb repressive complex 2 (PRC2) are common in MPNST.
- MPNST arises from NF1-deficient Schwann cells.
Purpose of the Study:
- To elucidate the oncogenic mechanisms driven by PRC2 loss in MPNST.
- To understand how PRC2 deficiency impacts chromatin and cellular identity.
Main Methods:
- Utilized engineered cells capable of dynamic PRC2 reassembly.
- Employed single-cell sequencing on clinical MPNST samples.
- Mapped transcriptional programs onto normal Schwann cell developmental trajectories.
Main Results:
- PRC2 loss remodels bivalent chromatin and enhancer landscapes, upregulating developmental transcription factors.
- PRC2 loss impairs type I interferon signaling and antigen presentation via Ras-STAT/IRF crosstalk.
- PRC2-deficient tumor cells exhibit a transcriptional profile resembling primitive mesenchymal neural crest stem cells.
Conclusions:
- PRC2 loss initiates a two-pronged oncogenic process in MPNST.
- This process involves chromatin remodeling and immune evasion, driving tumor aggressiveness.
- PRC2 deficiency enforces a dedifferentiated, stem cell-like state in MPNST cells.
More Related Videos
08:57Author Spotlight: Genetically Engineered Mouse Models and Pathological Characterization of Neurofibromatosis Type 1 Associated Tumors
Published on: May 17, 2024
09:37Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
