The regulation of hybrid-EMT and metastasis in colorectal cancer

Colorectal cancer is one of the commonest causes of cancer related death in the UK with metastasis (the spread of cancer cells to distant organs) the primary cause. For cancers to spread tumour cells need to invade into local tissues, break away from the primary tumour and then resettle at secondary sites. A process called epithelial to mesenchymal transition (EMT) is believed to be important for cancer spread but how it is controlled is poorly understood. This lack of knowledge impacts on our ability to develop new therapies that might inhibit it and provide benefit to patients.

The purpose of this research is to try to understand how the EMT process is initiated and in particular how tumour cells are maintained in an intermediate state thought to be important for metastasis. We aim to investigate in detail the function of the genes we have identified that we think control this process and discover whether they are important for metastasis. We also aim to directly test if this process is found in aggressive human cancers and whether it can help predict patient outcome. Importantly, we will also attempt to identify candidate molecules that drive metastasis that could be inhibited by therapeutic drugs. Together, this research will lead to increased understanding of how colorectal cancer spreads. This could lead to important advances in how to manage the most aggressive forms of this disease and ultimately lead to new therapies for its treatment. Furthermore, since tumour metastasis is the primary cause of death in many other cancer types it could have far reaching implications for the treatment of other cancers as well.

Colorectal cancer (CRC) is the second commonest cause of cancer mortality with the majority of deaths due to metastasis to distant organs. Epithelial-mesenchymal transition (EMT), the transition between epithelial and mesenchymal cell states, is an important mediator of metastasis. This process occurs though multiple intermediate states where cells maintain both epithelial and mesenchymal characteristics. These 'hybrid-EMT' states show high levels of phenotypic plasticity and are highly metastatic. Despite playing a key role in tumourigenesis how hybrid-EMT is induced is poorly understood. We have identified loss of the chromatin remodelling helicase Atrx as an inducer of hybrid-EMT and metastasis. Our initial analysis suggests that Atrx loss reduces activity of transcription factors important for maintaining epithelial cell function. Thus, we hypothesise that loss of epigenetic control of genes defining epithelial cell state is the key event initiating hybrid-EMT and an important mediator of metastasis. The aim of this research project is to test this hypothesis by determining the mechanisms that control the induction of hybrid-EMT and its relevance to tumour metastasis.

We will first determine the function of specific transcription factors in inducing hybrid-EMT and tumour metastasis, and determine how ATRX controls them. Using data from this analysis, we will generate a hybrid-EMT gene expression signature and determine whether this signature predicts survival in colorectal cancer patients. To complement these hypothesis driven experiments we will screen for novel mediators of hybrid-EMT using CRISPR and phospho-proteomics. These analyses will potentially identify candidate therapeutic targets for inhibiting hybrid-EMT and metastasis.

This research will increase our understanding of hybrid-EMT induction and tumour metastasis. Importantly, it has the potential to lead to critical insights into how to develop new therapies for its treatment.