Mitchell Grinwald
Program: Molecular Genetics and Genomics
Current advisor: Ting Wang, PhD
Undergraduate university: Washington University
Research summary
Transposable elements (TEs) are silenced by DNA methylation in somatic tissues but are dysregulated in patient tumors. Activated TEs can drive the formation of tumor-specific transcripts, which provide abundant opportunities for the development of gene and immunotherapies. Recent studies have linked PRC2-inactivating mutations to increased TE expression in human tumors, and PRC2-inhibiting drugs can drive ERV and LINE1 expression, accompanied by an interferon response in a variety of cancers. In Diffuse Midline Glioma (DMG) and Malignant Peripheral Nerve Sheath Tumor (MPNST), mutations that disrupt PRC2 function are highly recurrent and prognostically significant. I hypothesize that integrating PRC2 into existing models of tumor TE regulation will help define novel disease-specific TE therapeutic targets.
I analyzed Publicly available RNA-Seq data from 17 DMG and 41 MPNST patients to define TE subfamily and locus-specific transcription using TEtranscripts and TElocal. Additionally, TE-promoters and tumor-specific TE transcripts (TS-TETs) were identified across diseases and PRC2 mutation groups using TEProf3. PRC2-inhibiting mutations were associated with increased TE transcription across both tumor types. 10 previously discovered tumor-specific TS-TETs were identified in the MPNST samples, while 6 such TS-TETs were found in the DMG group. Several of these candidates were predicted to produce novel proteins, resulting in tumor-specific antigens. Follow-up experiments will establish the mechanism by which PRC2 regulates TEs in DMG and MPNST, while in vitro experiments will lay the groundwork for targeting TE-derived therapeutic vulnerabilities in these devastating diseases.
Graduate publications