Oncogenic signalling through transcriptional repression pathways in oesophageal adenocarcinoma.

Cancer is a disease caused by the malfunction of "normal cells" in our bodies. This causes the cells to change their characteristics and begin to grow uncontrollably and move around the body. These changes to cellular characteristics are ultimately driven by molecular changes in our cells. Usually our cells contain pathways which act to maintain their normal functions. However, in cancer cells, mutational damage leads to hyperactivation of several pathways. It is unclear how these hyperactive pathways lead to cancer and this project aims to determine how this occurs in the context of oesophageal cancer. One pivotal event leading to changes in our cellular characteristics is the widespread changes that occur in the expression of our genes, both through changing the on or off state through regulatory proteins known as activators or repressors respectively. Ultimately, in cancer cells, many genes which are normally off are turned on and vice versa, leading to phenotypic changes that are characteristic of cancer such as increased growth or altered metabolism. Much focus has been placed on understanding how the gene on state is achieved, however in this project we will focus on the off state and how this is controlled in the context of cancer. We will focus on a particularly deadly form of cancer, oesophageal adenocarcinoma, and investigate how one commonly deregulated pathway (the ERBB2 pathway) controls this process. This is important as drugs which target the ERBB2 pathway are currently used to treat a range of cancers but resistance often arises. By identifying and providing mechanistic insight into additional downstream target molecules and pathways, we are likely to uncover potential new therapeutic opportunities.

One of the key emerging molecular events which occur in the transition to oesophageal adenocarcinoma (OAC) is mutational activation of RTK pathway signalling pathway components. In particular ERBB2 locus amplifications are commonly found (>20% cases) but it is currently unclear what the molecular consequences of such amplifications are. One major pathway activated by ERBB2 signalling is the ERK MAP kinase pathway and it is known that a major impact of this pathway is on the transcriptional events in the nucleus. Our recent data implicate a number of ERK-regulated transcriptional repressor proteins as potentially important in OAC cells. However, we know very little about how these proteins operate in cancer and nothing about their function in OAC. Indeed, compared to transcriptional activation, much less is known about transcriptional repression in cancer and how oncogenic signalling pathways influence this activity. The overall aim of this study is to examine the role that transcriptional repression plays in deregulated oncogenic RTK pathway signalling in OAC. We will focus on the RTK-regulated CIC and ERF repressor proteins to gain mechanistic depth and, more generally, we will examine the role of silencer elements and 3D organisation of repressive regulatory hubs in OAC. We will first define the RTK-regulated transcriptional repression circuits in OAC and subsequently identify repressive silencer elements in the OAC genome. We will then derive a mechanistic understanding of the RTK pathway-driven changes to the repressive environment, by focussing on the 3D chromatin environment and the potential role of liquid-liquid phase separation. We will provide clinical relevance by relating our findings to molecular events found in OAC patients and by identifying new potential therapeutic target proteins and pathways lying downstream from oncogenic RTK signalling.