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

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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.