Polycomb repressive complex 2 (PRC2) is an essential epigenetic modifier mutated in several cancers and implicated in disease progression. PRC2 subunits, EED and SUZ12, are mutated in malignant peripheral nerve sheath tumors (MPNSTs), an aggressive, highly metastatic soft tissue sarcoma. In Chapter 1, I discuss the history of epigenetics and its roles in cancer development as it pertains to soft tissue sarcomas, specifically MPNSTs. I also discuss some challenges of treating sarcomas, completed and ongoing clinical trials utilizing epigenetic-based interventions, and promising preclinical epigenetic drug combinations. Finally, I consider future directions and how epigenetic crosstalk could be harnessed for MPNST treatment and monitoring.

In Chapter 5, I discuss some of the differences between SUZ12 and EED mutations regarding PRC2-dependent signaling and metastatic-like phenotypes. I also consider the alternate functions of SUZ12 and EED in other epigenetic complexes that contribute to epigenetic crosstalk in MPNSTs. I end this chapter and dissertation by outlining how multi-omics approaches paired with validation in different model systems could be used to identify biomarkers for sarcoma diagnosis, monitoring treatment response, and increasing therapeutic benefit.

Our group was one of the first to utilize CRISPR technology to generate somatic patient-relevant mouse models of sarcoma. In Chapter 4, I highlight some discrepancies in the new indel analysis technology available to the field. I conducted a side-by-side analysis of three common platforms using Nf1 sanger sequencing files. These findings have implications for the preclinical and clinical space as the number of CRISPR-based clinical trials increase and progress from ex vivo applications to in vivo editing.

In Chapter 3, I utilize publicly available datasets of gene expression and DNA methylation in sarcomas to interrogate PRC2-dependent mechanisms of epigenetic crosstalk. I have shown that loss of PRC2 correlates with a global hypermethylation profile, tumor microenvironment changes, and patient outcome. These findings have potential implications for biomarker development and patient outcomes in multiple sarcoma subtypes.

In Chapter 2, I describe how loss of PRC2 increases MPNST metastatic-like phenotypes in vitro, in mouse models of metastasis, and patient tumor samples. This phenotype can be rescued with pharmacological and genetic inhibition of key pro-metastatic genes, MMPs and LOXs, which are upregulated in a PRC2-dependent manner.