Abstract A024: PRC2 loss drives MPNST metastasis and matrix remodeling

Abstract

Abstract Epigenetic reprogramming alters gene transcription in response to different cellular cues and can occur at both the DNA level as well as histone post-translational modifications. Polycomb repressive complex 2 (PRC2) is a common epigenetic modifier that is responsible for adding methyl groups to the twenty-seventh lysine of histone 3. This modification is associated with decreased gene transcription and recruits complexes that further compact chromatin. PRC2 mutations have been implicated in the tumorigenesis of many cancer types; however, the role that PRC2 plays in tumorigenesis is complex and not well understood. PRC2 loss-of-function mutations have been identified in malignant peripheral nerve sheath tumors (MPNST), an aggressive sarcoma. PRC2 mutations are found in the EED and SUZ12 subunits in 70-92% of tumors. There are currently no effective therapies for MPNSTs resulting in a poor prognosis for individuals with inoperable tumors. Using a CRISPR/Cas9 system to delete EED or SUZ12, we developed in vitro and in vivo models to further study the biology of PRC2 loss in MPNSTs. Our data suggests that loss of PRC2 subunits increases the expression of extra-cellular matrix (ECM) remodeling genes, promotes cell migration in vitro, and increases pulmonary metastasis in vivo. We also observed that loss of either EED or SUZ12 increases collagen handling and a clustering metastatic phenotype. Additionally, loss of H3K27me3 was correlated with increased ECM and ECM remodeling genes as well as metastasis and overall survival in patient RNA-seq and tumor microarray data, respectively. Further characterization of the underlying mechanisms of PRC2-dependent metastasis will allow us to better understand the role of PRC2 in MPNST biology and test novel therapies for these patients. Citation Format: Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew Voigt, Alexandra Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher Stipp, Rebecca D. Dodd. PRC2 loss drives MPNST metastasis and matrix remodeling. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A024.