Cell extrinsic Polycomb-mediated epigenetic signaling in Melanoma

Epigenetic dysregulation has recently emerged as a common feature of most cancers. One group of epigenetic regulators implicated in Various types of cancer is the Polycomb group of proteins. Our preliminary data shows that epidermal-specific ablation of Polycomb activity in murine skin results in atypical melanocyte migration and epidermal pigmentation, reminiscent of dysplastic nevi (atypical mole) — a premalignant precursor and risk factor for the development of melanoma, the deadliest form of human skin cancer that develops from melanocytes. However, the mechanisms by which Polycomb activity in epidermal stem cells (EpSCs) modulates melanocyte behavior and melanoma pathogenesis are completely unknown.

By utilizing cutting-edge functional genomics combined with genetic mouse models, we will test our specific hypothesis that perturbation of Polycomb epigenetic activity in EpSCs modulates melanocyte oncogenic behavior, thereby promoting melanoma tumor initiation and progression. To this end, we plan to characterize the functional role of Polycomb activity in melanoma by perusing three specific aims:

Aim 1: Determine the role of epidermal Polycomb activity in melanoma tumorigenesis.

Aim 2: Elucidate the molecular crosstalk between EpSCs and melanocytes.

Aim3: Characterize the Polycomb—dependent alterations in the melanocyte epigenome controlling melanocyte behavior.

This proposal extends our ongoing collaboration toward understanding the roles of Polycomb in skin development and disease. The innovation of this grant lies in the identification of novel epigenetic signaling regulatory mechanism by which epidermal stem cells crosstalk with melanocytes. Elucidation of this crosstalk will shed light on processes leading to melanoma, the deadliest form of human skin Cancer.