Goran Micevic, MD, PhD

Lab website: https://miceviclab.github.io/home/

Melanoma is the deadliest form of skin cancer with an enormous toll on human life and health. It is estimated that nearly 10,000 deaths and 74,000 new cases of melanoma occurred in the United States alone in 2015, while 132,000 new melanoma cases were reported worldwide. Despite advancements in therapy, metastatic melanoma is an aggressive disease with a poor 5-year overall survival rate of approximately 17%.

1) Epigenetic changes in melanoma

Genetic changes in melanoma have been largely well described over the past decade, but epigenetic changes and their functional roles in melanoma formation remain, comparatively, poorly understood. DNA methylation is an epigenetic change that is almost universally abnormal in melanoma. However, the specific role of individual DNMT enzymes (DNMT1, DNMT3A and DNMT3B), their methylation targets in melanoma, and signaling pathways affected are largely elusive. We used a mouse model of melanoma based on the most common human mutation, BrafV600E, in the context of Pten tumor suppressor loss to investigate the role, signaling changes and targets of DNA methyltransferases during melanoma formation and progression. By inactivating individual DNA methyltransferases, functional requirements for DNMT enzymes during melanoma formation and progression were delineated, suggesting that DNMT3B is the crucial methyltransferase during melanoma formation, and may be a target for melanoma therapy. Dnmt3b is overexpressed in human melanoma, associated with shorter 5-year overall survival, and allows for long term activation of mTORC2 by silencing repressive miRNAs. Dnmt3b methylates genes marked by the histone modification H3K27me3, is an important regulator of global methylation in melanoma, and targets many genes well recognized to be aberrantly methylated in melanoma.

2) Prognostic factors of melanoma survival

Apart from mechanistic insights and potential therapeutic targets, we study methylation based gene signatures that can predict patient survival, and may be a valuable biomarker. In addition to focal hypermethylation, we studied the role of aberrant global hypomethylation in melanoma and found that it may be required for melanoma cell survival, as induction of hypermethylation leads to cell death.

3) Understanding epigenetic regulation immune response to melanoma

Currently, the most promising therapy for melanoma, and certain other cancers such as NSCLC, is antibody mediated inhibition of immune checkpoint pathways (Valpione and Campana, 2016). Epigenetic changes have been long recognized to regulate expression of antigen presentation genes, such as MHC Class I genes, tumor antigens. such as MAGE and NY-ESO1, and, more recently, viral response and interferon pathway activation (Licht, 2015).. Perturbing DNA methylation and other epigenetic modifications may provide a pathway to augmenting anti tumor immune responses. Others have shown that methylation regulates expression of PD-1, PD-L1, PD-L2 and CTLA-4 in MDS (Yang et al., 2014a). We recently found that PD-L1 methylation in melanoma is associated with patient survival (Micevic et al. 2019), and can be targeted using hypomethylating agents. Understanding the epigenetic changes contributing to T-cell exhaustion in melanoma -- and how to control them -- would significantly advance our understanding of response to current therapies.

Collectively, our studies are focused on the role of genetic and epigenetic changes in melanoma development and growth, including uncovering novel targets, developing prognostic tools and therapeutic strategies for the benefit of melanoma patients.