Oncoenhancers: hubs for early embryonic reprogramming in cancer (360G-Wellcome-202085_Z_16_Z)

Genome-wide studies have underscored a role for regulatory elements (REs) as cooperative facilitators or drivers of 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 (I dub 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. Promisingly, WT1-based immunotherapy clinical trials are underway. WT1 has topped a National Cancer Institute antigen prioritisation list because as a developmental regulator, 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. Here, we will use a well-established inducible RasG12V-transformed human mammary epithelial cell model (HMLER), where WT1 is abnormally reactivated, to a) identify using sequencing-based approaches and b) functionally characterise the WT1-associated oncoenhancers as an exemplar of RE reactivation in cancer. Future work will explore the functional relevance of oncoenhancers in maintaining the epithelial-mesenchymal balance upstream of WT1. The dissection of WT1-related oncoenhancers will be a paradigm for understanding dynamic embryonic enhancer malfunction in pathology.