Adaptation to Chronic Hypoxia in Triple-negative Breast Cancer

三阴性乳腺癌对慢性缺氧的适应

• 批准号: 2335478
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2335478
• 关键词: Adaptation; Chronic; Hypoxia; Triple; negative

Low levels of oxygen (i.e. hypoxia) are often observed in solid tumours. Hypoxia is able to drive several of the cancer hallmarks and promotes resistance to both radio and chemotherapy, resulting in its association with poor prognosis. Triple-negative breast cancer has the worst prognosis of all breast cancer subtypes with a 5 year survival rate of only 76.7%, and only 10.8% if the cancer has already metastasised. In line with this, triple-negative tumours often have higher levels of hypoxia than their hormone receptor expressing counterparts. The length and severity of hypoxia is heterogeneous both within and between tumours, meaning cells within the same tumour may experience both acute and chronic hypoxia. Acute hypoxia (<=24 hours) is relatively well studied, whereas research into chronic hypoxia (>= 7 days) is lacking. This project therefore aims to characterise the transcriptional response to chronic hypoxia using RNA sequencing. It also aims to identify proteins or microRNAs which are necessary for adaptation to chronic hypoxia using genome-wide CRISPR screening. This method enables specific vulnerabilities in hypoxic cells to be identified, meaning drugs can be designed to target these "Achilles heels".

在实体瘤中经常观察到低水平的氧（即缺氧）。缺氧能够驱动几种癌症标志，并促进对放射和化疗的抵抗，导致其与预后不良相关。三阴性乳腺癌是所有乳腺癌亚型中预后最差的，5年生存率仅为76.7%，如果癌症已经转移，则仅为10.8%。与此一致，三阴性肿瘤通常比其激素受体表达对应物具有更高水平的缺氧。缺氧的长度和严重程度在肿瘤内和肿瘤之间都是异质的，这意味着同一肿瘤内的细胞可能会经历急性和慢性缺氧。对急性缺氧（<=24小时）的研究相对较好，而对慢性缺氧（>= 7天）的研究则较少。因此，本项目旨在使用RNA测序来验证慢性缺氧的转录反应。它还旨在使用全基因组CRISPR筛选来识别适应慢性缺氧所必需的蛋白质或microRNA。这种方法能够识别缺氧细胞中的特定脆弱性，这意味着可以设计针对这些“阿基里斯之踵”的药物。