PRC2 Restricts Malignant Peripheral Nerve Sheath Tumorigenesis in a Genetically Engineered Mouse Model of MPNST

Area of Science:

• Oncology
• Epigenetics
• Cancer Biology

Background:

• Polycomb Repressive Complex 2 (PRC2) plays a dual role in cancer, acting as both an oncogene and tumor suppressor.
• Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor prognosis, often associated with loss of NF1, CDKN2A, and PRC2.
• Inactivating mutations in PRC2 core components (SUZ12, EED) are common in high-grade MPNSTs, contributing to oncogenesis, but the precise mechanisms are unclear.

Purpose of the Study:

• To investigate the role of PRC2 inactivation in MPNST pathogenesis within the sciatic nerve.
• To develop a genetically engineered mouse model that recapitulates human PRC2-loss MPNST.
• To elucidate the cellular and molecular mechanisms underlying PRC2-driven MPNST development.

Main Methods:

• Genetic inactivation of PRC2 component Eed, alongside Nf1 and Cdkn2a, in mouse Schwann-progenitor cells.
• Analysis of tumorigenesis in the sciatic nerve and other anatomical locations.
• Single-nucleus multiome sequencing to profile transcriptional changes in PRC2-deficient cells.

Main Results:

• Combined genetic inactivation of Eed, Nf1, and Cdkn2a in Schwann cells induced widespread sciatic nerve tumors in mice.
• Loss of Nf1 and Cdkn2a alone led to MPNST development in other locations but with longer latency.
• PRC2 loss reprogrammed Nf1/Cdkn2a-deficient Schwann cells into a dedifferentiated, neural crest stem cell-like state, mirroring human MPNST transcriptomes.

Conclusions:

• PRC2 exhibits context-dependent tumor suppressive functions within the sciatic nerve.
• A novel mouse model accurately replicates human PRC2-loss MPNST.
• This model facilitates further mechanistic studies and preclinical investigations of MPNST driven by PRC2 loss.