Oncoenhancers: hubs for early embryonic reprogramming in cancer

Genome-wide studies have underscored a role for regulatory elements (REs) in driving tumour progression. This is partly because structural/epigenetic alterations to REs appear to reactivate dormant embryonic processes such as stemness leading to chemoresistance, metastasis and dormancy. However, the reactivated REs, or ‘oncoenhancers’, and the mechanisms regulating their early hijack remain unexplored. Therefore, I propose to build on my previous findings to delineate and characterise oncoenhancers reactivating the Wilms’ tumour protein (WT1) in epithelial cancers.

WT1 has topped a National Cancer Institute antigen prioritisation list because its well-documented expression in adult tissues is restricted to few non-epithelial cell types yet it is abnormally reactivated uniquely in epithelial cancer cells. We will use a human mammary epithelial cell model (HMLER), where WT1 is abnormally reactivated, to identify using sequencing-based approaches and functionally characterise the WT1-associated oncoenhancers as an example of RE reactivation in cancer.

This work will provide some understanding of dynamic embryonic enhancer malfunction in pathology. Future work will explore the functional relevance of oncoenhancers in maintaining the epithelial-mesenchymal balance upstream of WT1.