Investigating the Role of Cancer-Associated Fibroblasts in Remodeling the Melanoma Tumor Microenvironment  

Melanoma is the most lethal skin cancer, and the success of current therapies remains limited. To better tailor melanoma treatments, we must understand the complexity of the tumor microenvironment (TME). Within the TME, many different types of cells interact with each other, including immune cells, tumor cells, and stromal cells. The stroma is composed of the structural components that support the tumor tissue. A key component of the stroma are cancer-associated fibroblasts (CAFs), which can control tumor growth, blood supply, protection from the immune system, or the ability to metastasize. However, these CAFs are complex and can display tumor-promoting or tumor-restraining functions. For example, inflammatory CAFs attract defective immune cells that can promote tumor growth, while myofibroblastic CAFs form barriers to tumor cell invasion and spread.

It remains unclear how these different types of CAFs develop from normal skin fibroblasts and how CAF identity and functionality is shaped.   Despite the growing importance of CAFs in tumor biology, our understanding of their ‘epigenetic’ regulation is extremely limited. Epigenetics is the study of the processes that control how and when genes are turned on or off and is critical for shaping cellular identity. Here, we will use cutting-edge high-resolution approaches to study the epigenetic features that control CAF identity. Using mouse models of melanoma that mimic the complexity of the TME, we will use spatially resolved approaches to ‘observe’ cellular interactions and behaviors within the tumor as the melanoma develops. We will focus on inflammatory CAFs, which we showed can lead to an impaired anti-tumor immune response and increased tumor growth in mice. Our proposed work could reveal the presence of CAFs that inhibit immune function and indicate approaches to dampen their pro-tumor features, as some epigenetic regulators can be effectively targeted with drugs. Thus, a deeper understanding of the tumor stroma can lead to novel therapeutic approaches for melanoma patients.