Adaptation to Chronic Hypoxia in Triple-negative Breast Cancer

在实体瘤中经常观察到低水平的氧（即缺氧）。缺氧能够驱动一些癌症特征，并促进对放疗和化疗的抵抗，导致其与不良预后相关。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，三阴性肿瘤通常比表达激素受体的肿瘤具有更高的缺氧水平。缺氧的时间长短和严重程度在肿瘤内部和肿瘤之间都是不同的，这意味着同一肿瘤内的细胞可能经历急性和慢性缺氧。急性缺氧（<=24小时）的研究相对较好，而慢性缺氧（>= 7天）的研究缺乏。因此，该项目旨在利用RNA测序来表征对慢性缺氧的转录反应。它还旨在利用全基因组CRISPR筛选鉴定适应慢性缺氧所必需的蛋白质或microrna。这种方法可以识别出缺氧细胞中的特定弱点，这意味着可以设计针对这些“阿喀琉斯之踵”的药物。

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".