Mechanistic understanding of how obesity causes cancer – Research project #1: What are the properties of cancer cells adapted to aberrant physiological environments?

Obesity increases the risk of developing thirteen types of cancer that normal weight individuals may not develop despite of harbouring the same cancer risk loci. Globally, overweight/obesity may account for 544 300 cancer cases every year and is currently implicated in 15-20% of cancer-related mortalities. This places obesity second only to smoking as the most prevalent preventable cause of cancer.

We have previously demonstrated that obesity is not associated with additional oncogenic genetic alterations that could explain the increased cancer risk. Instead, we demonstrate that cancer cells undergo adaptive epigenetic remodelling and gain tumour initiating properties when exposed to prolonged periods of obese conditions. This interaction between metabolic, epigenetic, and tumorigenic events currently represents significant knowledge gaps.

AIM

The aims are to:

• Uncover the relationship between systemic metabolic challenge as induced by physiological stressors and intracellular metabolite dynamics in cancer cells.
• Identification of the metabolites that are sufficient to drive tumour initiation – and how this is achieved.
• Determine how metabolite-driven epigenetic changes can display loci specificity.
• Discover the epigenetic, transcriptional and translational machinery required to that link physiological stressor to tumour initiation.

APPROACH

Key methodologies for this project are in vivo CRISPR loss- and gain-of-function screens, single cell transcriptomics and epigenomics, in vivo tumour modelling and metabolomic tracer studies.