How are meiotic genes re-activated in cancer and can we exploit this in the clinic?

在正常情况下，生殖蛋白确保婴儿从母亲（通过卵子）和父亲（通过精子）那里获得一半的遗传物质DNA。这意味着婴儿含有母亲和父亲基因的混合物。生殖蛋白被认为只存在于参与生殖的器官中，在人体中没有其他已知的作用。出乎意料的是，我们最近发现其中一些被称为“SC蛋白”的生殖蛋白也存在于癌细胞中。此外，当SC蛋白水平高时，患者的疾病侵袭性更强，死亡时间也更早。目前，我们还不清楚癌细胞为什么以及如何制造这些生殖蛋白。然而，我们观察到，用于治疗某些癌症的化学疗法会导致生殖因素重新启动。这反过来又会导致治疗抵抗和癌症恶化。我们的目标是确定SC蛋白在癌症中是如何被重新激活的，以及哪种化疗方法会导致SC蛋白被激活。我们将通过三件作品来解决这些问题，每件作品都有特定的目的。目的1。表征癌症中SC启动子产生的启动子结合蛋白。细胞内蛋白质的产生是通过激活蛋白质——启动子结合蛋白——与编码蛋白质的DNA相互作用来触发的。细胞有各种各样的启动子结合蛋白。我们将使用我的实验室开发的一种新方法来发现哪些启动子结合蛋白与编码SC蛋白的DNA相互作用并激活蛋白质生产。目标2。表征癌症中参与SC再表达的调节网络。正确的启动子结合蛋白在正确的时间被激活是至关重要的。每种类型的启动子结合蛋白的可用性是由其他蛋白质的网络控制的。因此，这种蛋白质网络可以间接影响SC蛋白是否在癌细胞中产生。在本部分的工作中，我们将使用实验室和计算实验的组合来表征负责SC蛋白生产的蛋白质网络。目标3。确定哪种抗癌疗法激活SC表达及其对治疗结果的影响。最后，我们将进行实验，分析在一系列常用抗癌疗法的存在下，癌细胞中产生的SC蛋白水平。我们将确定导致SC蛋白在癌细胞中产生的治疗方法，并确定SC蛋白产生对耐药性发展的影响。我们的项目对未来的癌症治疗具有重要意义。目前，英国每年有超过16.6万人死于癌症。对化疗产生耐药性以及由此导致的治疗失败是导致90%死亡的原因。我们的研究将有助于确定那些癌症变得耐药的人，从长远来看，这将为防止耐药性发展的新药铺平道路。此外，癌症治疗的主要挑战之一是选择性地杀死肿瘤细胞，同时保留健康细胞。不幸的是，大多数抗癌治疗也会杀死健康细胞，这就是导致恶心和虚弱等副作用的原因。由于生殖蛋白在正常健康器官中不存在，它们可能成为开发抗癌药物的重要新靶点。杀死表达这些蛋白质的癌细胞可能是特异性的，并保护健康的非癌细胞，从而减少对患者的副作用。

Under normal circumstances, reproductive proteins make sure that a baby receives half of its genetic material, DNA, from the mother (through the egg) and half from the father (through the sperm). This means that the baby contains a mixture of both their mother's and father's genes. Reproductive proteins are believed to be present only in organs that take part in reproduction and have no other known roles in the body.Unexpectedly, we recently discovered that some of these reproductive proteins, known as 'SC proteins', are also found in cancer cells. Furthermore, when the levels of SC proteins are high, patients have a more aggressive disease and die earlier. Currently, we do not understand why and how cancer cells make these reproductive proteins. However, we have observed that chemotherapies used to treat certain cancers can cause reproductive factors to turn back on. This, in turn, can lead to therapy resistance and worsening of the cancer. Our goal is to determine how SC proteins are switched back on in cancer, and which chemotherapies cause the proteins to be switched on. We will address these questions through three pieces of work, each with specific aims.Aim 1. Characterise promoter binding proteins responsible for SC promoter production in cancer.Production of a protein inside a cell is triggered by activating proteins - promoter binding proteins - interacting with the DNA which encodes the protein. Cells have a wide range of promoter binding proteins. We will use a novel approach developed in my lab to discover which promoter binding proteins interact with DNA encoding SC proteins and activate protein production.Aim 2. Characterise the network of regulators involved in SC re-expression in cancer.It is essential that the correct promoter binding proteins are active at the right time. The availability of each type of promoter binding protein is controlled by a network of other proteins. This network of proteins can therefore indirectly affect whether SC proteins are made in cancer cells. In this section of work we will use a combination of laboratory and computational experiments to characterise the protein networks responsible for SC protein production. Aim 3. Determine which anti-cancer therapeutics activate SC expression and the impact this has on treatment outcome.Finally, we will perform experiments analysing the levels of SC proteins produced in cancer cells in the presence of a range of commonly-used anti-cancer therapies. We will identify therapies that cause SC proteins to be made in cancer cells, and also establish the impact SC protein production has on resistance development.Our project has important implications for future cancer treatment. Currently, more than 166,000 people die from cancer in the UK each year. Becoming resistant to chemotherapy and the resulting treatment failure is responsible for 90% of these deaths. Our research will help to identify those whose cancers are becoming treatment resistant and - in the longer term - paves the way for new drugs to prevent resistance developing.In addition, one of the main challenges in cancer treatment is to selectively kill tumour cells whilst sparing healthy cells. Unfortunately, most anti-cancer treatments also kill healthy cells, which is the reason for side-effects like nausea and weakness. As reproductive proteins are absent in normal healthy organs, they could be important new targets for the development of anti-cancer drugs. Killing cancer cells that express these proteins might be specific, and protect healthy non-cancer cells, resulting in less side-effects for patients.