Mentor: Rebecca Dodd, PhD
Year Entered into Program: 2018
Terminal Degree(s) Received and Year: PhD 2023
Research Description
The functional role of PRC2 loss in MPNST Metastasis
My thesis project is focused on investigating the mechanisms of epigenetic-induced metastasis using isogenic cell lines and various murine models including orthotopic allografts, xenografts, and a CRISPR/Cas9 tumorigenesis model. Using CRISPR/Cas9, the Dodd lab is developing an in vivo somatic tumor model of Polycomb Repressive Complex 2 (PRC2) loss. Currently, the only published mouse model of PRC2 loss in malignant peripheral nerve sheath tumors (MPNST) is a germline knockout model with heterozygous Nf1, p53 and Suz12 mutations. This project will include characterization of PRC2 activity dysregulation in MPNSTs using this state of the art somatic CRISPR/Cas9 tumorigenesis approach.
PRC2 Complex Activity: Epigenetic reprogramming is a complex, multi-level regulatory process that integrates DNA methylation at gene promoters and post-translational modifications of histones to alter gene transcription [2, 3]. PRC2 is a common epigenetic modifier that is a multi-subunit complex that adds methyl- groups to the twenty-seventh lysine of histone 3 (H3K27me1,2,3). This modification results in condensed chromatin and decreased transcription of genes. The core complex of PRC2 that is necessary and sufficient to methylate H3K27 includes EED, SUZ12, and EZH1/2 [3, 4]. Mutations in either of these subunits results in loss of H3K27 methylation.
PRC2 Dysregulation and MPNST Metastasis: PRC2 mutations have been implicated in the development and progression of many cancer types. When mutations in PRC2 were first described, PRC2 was believed to behave strictly as an oncogene. However, the role that PRC2 plays in cancer biology is complex and not well understood [5]. PRC2 loss-of-function mutations have been identified in malignant peripheral nerve sheath tumors (MPNST), an aggressive soft tissue sarcoma. MPNSTs comprise ~5-10% of all soft tissue sarcomas and arise from the myelinating nerve sheath of peripheral neurons. The median age for MPNST incidence is between 20-60 years of age [6]. The early onset of this cancer distinguishes this pathology from common aged-associated phenotypes that are observed in other cancers. PRC2 mutations are found in the EED and SUZ12 subunits in 70-92% of tumors [7, 8]. There are currently no effective therapies for MPNSTs resulting in a poor prognosis for individuals with inoperable and metastatic tumors. Our preliminary data suggests that dysregulation of PRC2 activity increases the expression of extra-cellular matrix remodeling proteins, promotes cell migration in vitro, and increases pulmonary metastasis in vivo. My project will focus on interrogating the mechanism for PRC2-dependent metastasis. This work will result in a better understanding PRC2 function and the development of novel therapies for these patients.
Awards
- University of Iowa Roy J. and Lucille J. Carver College of Medicine Inclusive Excellence Fellowship, 2018
- Fellowship appointment on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2019-2022
- University of Iowa Molecular Medicine Research Retreat Poster/Slam Slide Presenation Award Recipient, 2020
Publications
- Xuelian Tan, Yuqi Zhu, Xuxing Shen, Qierra Brockman, Can Li, Yogesh Jethava, Dingming Huang, Ivana Frech, Guido Tricot, and Fenghuang Zhan.: Macrophages Serve as an Iron Reservoir for Myeloma Tumor Cells. Haematologica; HAEMATOL/2019/229203. This publication was submitted and currently working on revisions.
- Wu, C., Zhang L., Brockman, Q.R., Zhan, F., and Chen, L.: Chimeric Antigen Receptor T Cell Therapies for Multiple Myeloma. J Hematol Oncol 12(1):120, 2019. PMCID: PMC6873434