Are different AP-1 subunit heterodimers associated with colorectal cancer patient outcome, metastasis and tumour hypoxia?

结直肠癌是第三种最常见的癌症，每年导致全球50万人死亡。结直肠癌通常含有低氧区域(缺氧)。肿瘤缺氧是由高增殖率和低血管形成引起的。肿瘤缺氧与治疗耐药、转移增加和患者生存不良有关。寻找针对低氧肿瘤的新方法是提高患者存活率的关键。我们最近发现AP-1是缺氧性肿瘤存活和生长的主要调节因子。AP-1是由Fos和Jun蛋白亚基异源二聚形成的转录因子。这些异源二聚体的功能是不可互换的，AP-1异源二聚体的靶基因也不同。AP-1靶基因调控癌症表型的主要特征。在这个项目中，我们的目标是使用一种新的成像方法来量化AP-1异二聚体的水平，这种方法允许对患者肿瘤样本中的蛋白质状态进行功能表征。我们将确定哪些AP-1异源二聚体与结直肠肿瘤的缺氧、转移和患者生存有关。我们还将研究临床相关的AP-1亚单位的功能作用。我们将在结直肠癌细胞系中使用AP-1亚单位的CRISPR Cas9基因敲除，并研究包括三维生长和肿瘤侵袭在内的癌症表型。

Colorectal cancer is the third most common cancer leading to 500,000 deaths a year worldwide. Colorectal cancers frequently contain regions of low oxygen (hypoxia). Tumour hypoxia is caused by high proliferative rates and poor vascularisation. Tumour hypoxia is associated with therapy resistance, increased metastasis and worse patient survival. Identifying novel approaches to target hypoxic tumours is key to improving patient survival. We recently identified that AP-1 is a major regulator of hypoxic tumour survival and growth. AP-1 is a transcription factor formed by the heterodimerisation of FOS and JUN protein subunits. The function of these heterodimers is not interchangeable and target genes of the AP-1 heterodimers differ. AP-1 target genes regulate major hallmarks of cancer phenotypes. In this project we aim to quantify AP-1 heterodimer levels using a novel imaging approach that allows functional characterisation of protein states in patient tumour samples. We will identify which AP-1 heterodimers are associated with colorectal tumour hypoxia, metastasis and patient survival. We will also investigate the functional role of clinically relevant AP-1 subunits. We will use CRISPR CAS9 gene knockouts of AP-1 subunits in colorectal cancer cell lines and investigate cancer phenotypes including 3-Dimensional growth and tumour invasion.