Oncogenic signalling through transcriptional repression pathways in oesophageal adenocarcinoma.

癌症是一种由我们体内的“正常细胞”功能失调引起的疾病。这会导致细胞改变它们的特性，开始不受控制地生长，并在身体周围移动。这些细胞特征的变化最终是由我们细胞中的分子变化驱动的。通常，我们的细胞含有维持其正常功能的途径。然而，在癌细胞中，突变损伤导致几种途径的过度激活。目前还不清楚这些过度活跃的通路如何导致癌症，该项目旨在确定这在食管癌的背景下是如何发生的。导致我们细胞特征变化的一个关键事件是我们基因表达的广泛变化，这两种变化都是通过分别称为激活子或阻遏子的调节蛋白改变开启或关闭状态。最终，在癌细胞中，许多通常关闭的基因被打开，反之亦然，导致癌症特征的表型变化，如生长增加或代谢改变。人们的注意力主要集中在了解基因的开启状态是如何实现的，然而在这个项目中，我们将重点关注关闭状态以及在癌症背景下如何控制它。我们将专注于一种特别致命的癌症形式，食管腺癌，并研究一种常见的失调途径（ERBB2途径）如何控制这一过程。这一点很重要，因为靶向ERBB2通路的药物目前被用于治疗一系列癌症，但往往会产生耐药性。通过识别和提供对其他下游靶分子和途径的机制见解，我们可能会发现潜在的新治疗机会。

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.