Single-cell sequencing reveals activation of core transcription factors in PRC2-deficient malignant peripheral nerve sheath tumor

• Published in: Cell reports (Cambridge) 2022-09, Vol.40 (12), p.111363, Article 111363
• Main Authors: Zhang, Xiyuan, Lou, Hannah E., Gopalan, Vishaka, Liu, Zhihui, Jafarah, Hilda M., Lei, Haiyan, Jones, Paige, Sayers, Carly M., Yohe, Marielle E., Chittiboina, Prashant, Widemann, Brigitte C., Thiele, Carol J., Kelly, Michael C., Hannenhalli, Sridhar, Shern, Jack F.
• Format: Article
• Language: English
• Subjects: bivalent gene; Carcinogenesis; Chromatin; FOXC1; HOXB8; Humans; Interferon Regulatory Factors - genetics; Interferon Type I - genetics; neural crest stem cell; neurofibromatosis type 1; Neurofibrosarcoma - genetics; NF1; polycomb repressive complex 2; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; PRC2; single-cell sequencing; transcription factor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111363

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. [Display omitted] •PRC2 loss activates bivalent genes via transcriptional recruitment of active enhancers•PRC2 loss activates core TFs required to sustain the MPNST oncogenic program•PRC2-null MPNSTs mimic Schwann cell progenitors and reduce antigen presentation•scRNA-seq reveals heterogeneity within the MPNST microenvironment Zhang et al. provide evidence that PRC2 loss activates cell-fate-determining transcription factors by recruiting active enhancers and dampens type I interferon signaling and antigen presentation through transcriptional cross talk with the hyperactivated Ras. These observations are supported by integrative analysis of single-cell sequencing of patient MPNST samples.