Epigenetic regulators of cancer
The skin is our body's first line of protection. The increase in environmental stressors such as UV, chemical carcinogens, and pathogens has several detrimental outcomes for skin cancer, including squamous cell carcinoma, Merkel cell carcinoma, and melanoma.
Epigenetic Regulation of Squamous Cell Carcinoma (SCC)
SCC is one of the most common skin cancers. As more and more oncogenes are discovered in SCC tumorigenesis, we find that they are not mutant but instead are highly expressed via epigenetic changes in the tumor. However, there are few studies about the epigenetic mechanisms involved in controlling tumorigenesis. We are interested in uncovering the epigenetic regulation that controls the transition of epidermal cells from normal to cancer cells in both mouse and human SCC. By performing cutting-edge, high-throughput methods using primary human SCC tumors, we identified the alteration of epigenetic modifications and teased out the epigenetic regulators/target genes involved in SCC tumorigenesis. We also use transgenic and xenograft mouse models to test how the gain or loss of function of key epigenetic regulators impacts tumor initiation and progression mechanism in vivo. Lastly, we culture cancer cells in vitro and in vivo tumor transplant models to test the candidate drugs inhibiting tumor progression. Epigenetic regulation is a reversible process; it is critical to understand the epigenetics of cancer biology to find potential therapeutic methods that revert SCC formation by altering epigenetic regulation.
Cell of origin and regulation of Merkel cell carcinoma
We are one of only a handful of labs studying Merkel cell carcinoma (MCC), a rare skin disease driven by virus oncogenes. We use transgenic mouse models to study MCC tumor initiation, seeking to understand what cell types can become MCCs and how they are reprogrammed into cancer. Through this project, we discovered a population of cells in the hair follicle that can be reprogrammed to an MCC-like phenotype. In the future, spatial and single-cell transcriptomics will help us identify these cells and understand the biology of MCC tumor initiation.
Additionally, we use in vitro cell culture, mouse xenografts, and patient tumor samples to test novel therapeutic drugs, in the process not only discovering more effective treatments but also learning more about the epigenetic landscape of MCC.
The role of environment cells in melanoma progression
Melanoma is an aggressive skin cancer with a 20% survival rate when metastasized, primarily originating in sun-exposed areas due to UV radiation, a known carcinogen that damages DNA. While melanoma often arises in melanocytes with sun-damaged DNA, we have uncovered a novel mechanism by which UV may contribute to melanoma formation by impacting the cells neighboring melanocytes instead. Our preliminary studies indicate that epidermal cells, the neighboring cells of melanocytes in the skin, influence melanocyte behavior and can promote melanoma development. Typically, the Polycomb repressor complex prevents epidermal cells from expressing and secreting proteins that promote melanocyte activation and melanoma formation. UV irradiation disrupts Polycomb expression in epidermal cells, leading to the secretion of these proteins that promote abnormal melanocyte behavior. To explore this further, we will use mouse models to investigate how Polycomb loss in the epidermis influences melanoma tumor formation and progression, and we will analyze human melanoma samples to identify the secreted proteins responsible for this altered melanocyte behavior. These studies aim to uncover the signaling pathways between the epidermis and melanocytes, potentially paving the way for preventative approaches targeting epidermal cells in melanoma.
Epigenetic processes in the control of uveal melanoma metastasis
Uveal melanoma (UM), though a rare form of human cancer, is the second most common type of melanoma. In about half of the cases, UM metastasizes to other parts of the body, which can be fatal. UM tumors are classified into two risk groups: low-risk (class 1) and high-risk (class 2). A key step in improving the management of UM is to understand the factors that make the high-risk group more dangerous, the molecular changes that lead to disease progression, and identifying treatments to target these aggressive tumors. Research has identified that alterations in the BAP1 gene are a hallmark of more aggressive UM, occurring in over 80% of high-risk cases. These genetic changes drive tumor aggressiveness, but they also present potential vulnerabilities that could be exploited for therapeutic purposes. We aim to investigate the molecular consequences of BAP1 alterations in UM cells and explore various drugs and genetic strategies to reverse these changes. Ultimately, we will assess whether these interventions can inhibit the growth of UM cells and reduce mortality in affected patients.