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Objective: Recurrent mutations in the polycomb repressive complex 2 (PRC2) occur in ~80% of malignant peripheral nerve sheath tumors (MPNST), which originate from NF1-deficient Schwann cells. In MPNST, PRC2 loss results in a diverse set of transcriptomic and phenotypic consequences, including gain of acetylated H3K27 (H3K27ac) accompanying the loss of trimethylated H3K27 (H3K27me3), hyperactivated Ras signaling, and tumor escape from immune surveillance. Mechanistic understanding of how PRC2 loss results in these diverse consequences remains unresolved. Methods: To delineate the oncogenic mechanisms mediated by PRC2 loss, we engineered MPNST cell lines to dynamically reassemble a functional PRC2 and evaluated the transcriptomic and epigenetic consequences of PRC2 restoration. We further extended these finding using single cell RNA sequencing (scRNAseq) from human MPNST. Results: Through integrative analysis of RNAseq and H3K27me3 ChIP-seq in PRC2-deficient MPNST cells, we identified 6134 H3K27me3 peaks gained when a functional PRC2 was restored. Of the 876 significantly altered genes, 699 genes were downregulated, and 177 genes were upregulated when a restored PRC2 caused genome-wide redistribution of H3K27me3 peaks. Detailed mechanistic dissection of these PRC2-regulated genes revealed a two-pronged oncogenic process mediated by PRC2 loss and they cooperatively contribute to the tumorigenesis of MPNST. First, PRC2 loss leads to the upregulation of a transcriptional circuit that remodels the enhancer landscape of MPNST cells and establishes an enhancer-driven transcription factor, FOXC1, as a master regulator and thus a core vulnerability of the cell. Second, PRC2 loss reduces type I interferon (IFN) signaling and antigen presentation as a downstream consequence of the upregulated Ras signaling. These data were further integrated with scRNAseq of human MPNST. Importantly, we discovered that the PRC2-deficient tumor cells have a corrupted transcriptional program characteristic of a mesenchymal precursor cell found during the trajectory of normal Schwann cell development. Interestingly, malignant cells expressing high levels of IFN and antigen presentation genes were missing in the metastatic MPNST, potentially allowing the tumor cell to escape the immune surveillance. The transcriptional circuit established by PRC2-regulated FOXC1 and its downstream targets sustains the malignant program in both primary and metastatic MPNST. Conclusion: In summary, we discovered the activation of a lineage specific oncogenic transcription program in PRC2-deficient MPNST, which is characteristic of a neural crest-derived mesenchymal stem cell. Our findings provide mechanistic understanding of the inherent metastatic potential, chemotherapy and radiotherapy resistance, and immune escape that are clinically characteristic of these tumors. Citation Format: Xiyuan Zhang, Hannah E. Lou, Vishaka Gopalan, Zhihui Liu, Hilda Jafarah, Haiyan Lei, Paige Jones, Carly M. Sayers, Marielle E. Yohe, Prashant Chittiboina, Brigitte C. Widemann, Carol J. Thiele, Michael C. Kelly, Sridhar Hannenhalli, Jack F. Shern. Loss of PRC2 enforces a mesenchymal neural crest stem cell phenotype in NF1-deficient cancer through activation of core transcription factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 701. |
