Mitchell Grinwald

Program: Molecular Genetics and Genomics

Current advisor: Ting Wang, PhD

Undergraduate university: Washington University, 2020

Enrollment year: 2021

Research summary
Defining the Role of Polycomb Repressive Complex 2 in Regulating Transposable Element Activation in Malignant Peripheral Nerve Sheath Tumor

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 other epigenetic mechanisms including Polycomb Repressive Complex 2 (PRC2) may provide a backup method of TE repression in human cancers. I am collaborating with Dr. Angela Hirbe and Dr. Ben Garcia 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.
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. My analysis of 150 MPNST and nerve sheath tissue sample transcriptomes from these datasets 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. I am currently integrating additional publicly available tumor transcriptomes to comprehensively charecterize the Te expression landscape of MPNST. I am performing additional, ongoing analysis to identify MPNST TS-TEA candidates.
Through a collaboration with Ben Garcia’s lab, I have used a PRC2-LOF and isogenic, doxycycline inducible PRC2-rescue cell line to assess the effects of DNMTi and PRC2-LOF on TE regulation in isolation and in combination in MPNST. Previous studies in MPNST and other cancers have assessed TE expression after 4-6 days of treatment with DNMTi. Emerging evidence suggests that mechanisms for tolerance of TE expression and epigenetic compensation for loss of DNA methylation may develop over longer time periods. My experimental approach is the first to extend the DNTMi treatment and observation window from 6 days to 14 days, with multiomics characterization of cell line responses at D0, D6, and D14 of DNMTi treatment. Preliminary transcriptomic data and analysis suggest that TE dysregulation is a dynamic process that continues to evolve past D6 of DNMTi treatment. This experiment provides a valuable opportunity to broaden the field’s understanding of TE regulation and cancer responses to epigenetic therapy both through PRC2-dependent and PRC2-independent tolerance mechanisms. Sequencing experiments and data analysis is ongoing.
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. This effort is also progressing, and I plan to perform proof-of-concept and limiting dilution experiments throughout the summer of 2025 to optimize the assay before advancing to high-throughput charecterization of known infectious disease antigens and novel neoantigens.

Graduate publications