Oncogenic signalling through transcriptional repression pathways in oesophageal adenocarcinoma.

癌症是一种由人体内“正常细胞”功能障碍引起的疾病。这会导致细胞改变其特性，开始无法控制地生长并在身体周围移动。细胞特性的这些变化最终是由我们细胞中的分子变化驱动的。通常，我们的细胞包含维持其正常功能的通路。然而，在癌细胞中，突变损伤会导致几条途径的过度激活。目前还不清楚这些过度活跃的通路是如何导致癌症的，这个项目的目的是确定这是如何在食道癌的背景下发生的。导致我们细胞特性变化的一个关键事件是我们的基因表达发生了广泛的变化，这两种变化都是通过分别称为激活物或抑制物的调节蛋白来改变开启或关闭状态。最终，在癌细胞中，许多正常关闭的基因被打开，反之亦然，导致癌症特有的表型变化，如生长加速或新陈代谢改变。很多人把重点放在了解基因开启状态是如何实现的，然而在这个项目中，我们将重点放在关闭状态以及如何在癌症背景下对其进行控制。我们将重点研究一种特别致命的癌症--食管腺癌，并研究一个常见的非调控途径(ERBB2途径)是如何控制这一过程的。这一点很重要，因为针对ERBB2途径的药物目前被用于治疗一系列癌症，但往往会出现耐药性。通过识别和提供对额外下游靶分子和途径的机械性洞察，我们很可能发现潜在的新的治疗机会。

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.