Mitchell Grinwald
Program: Molecular Genetics and Genomics
Current advisor: Ting Wang, PhD
Undergraduate university: Washington University
Research summary
Transposable elements (TE) are derepressed in cancer and can give rise to therapeutic vulnerabilities including tumor-specific TE antigens (TS-TEAs). TS-TEAs are primarily repressed by DNA methylation, but emerging evidence suggests that Polycomb Repressive Complex 2 (PRC2) may provide a complementary method of TE repression in human cancers. I am collaborating with Dr. Angela Hirbe to investigate TE and TS-TEA regulation in malignant peripheral nerve sheath tumor (MPNST), an incurable cancer in which PRC2 compromising mutations are highly recurrent and prognostically significant. These efforts will provide the first direct investigation of whether PRC2-mediated H3K27me3 directly regulates TEs in human cancer, and may provide a rationale for combinatorial PRC2 inhibitor and DNA methyltransferase inhibitor (DNMTi) therapy in patients with PRC2 WT tumors.
My preliminary analyses of public transcriptomic MPNST datasets have demonstrated that PRC2-WT and PRC2-LOF MPNST tumors express partially distinct populations of TE-transcripts, and that these features are sufficient to distinguish WT from LOF tumors. Through DUA and MTA agreements with the Neurofibromatosis Therapy Acceleration Program (NTAP) and the Genomics of MPNST consortium (GeM), I’ve assembled the largest collection of MPNST transcriptomic data to date. I will use these data to comprehensively describe the TE and TS-TEA landscape of MPNST, and to identify widely shared TS-TEAs for further investigation. We will leverage cutting-edge patient-derived xenograft models developed by the Hirbe lab to describe tumor and TE responses to DNMTi epigenetic therapy. We will leverage cutting-edge enhanced gene-body coverage single-cell RNA sequencing techniques to profile TE and TS-TEA expression in these tumor models. These data will provide insight into the heterogeneity of TE regulation in patient tumors, and how epigenetic therapy influences the degree to which TS-TEAs are shared among tumor subclones.
The Wang lab has predicted thousands of TS-TEAs from a large pan-cancer cohort, and many of these TS-TEAs are widely shared between patients. Other pioneering studies have shown that TS-TEAs can stimulate potent and partially recurrent immune responses across healthy donors and patients with cancer. Together these groundbreaking findings suggest TS-TEAs are a new class of shared neoantigens with great potential for the development of off-the-shelf, generalizeable, immunotherapies. In order to efficiently prioritize high-quality TS-TEAs for further research and immunotherapy development, I am developing a high-throughput functional assay to identify immunogenic TS-TEAs. I am collaborating with my classmate Michael Moore, and Dr. Rui Tang for this second project.
Graduate publications