Vision

People with type 2 diabetes (T2D) and obesity have an increased risk of getting and dying from certain types of cancer. Yet currently there are no cancer prevention and treatment strategies that are tailored to people with T2D.

People with T2D have abnormal levels of metabolites in their blood throughout disease development. We are particularly interested in how this might drive cancer promotion and progression. Cancer is a disease of reprogrammed metabolism and the metabolic abnormalities of the host circulation are likely intrinsically linked to the probability a cancer develops and the characteristics of the cancer cells. Given the dramatically increasing prevalence of T2D, both the associated elevated cancer risk and underlying biological basis for T2D associated tumorigenesis need to be defined. 

Mission

We aim to address which cancers develop as a result of the metabolic environment characteristic of T2D and how they do so. We hope this will in turn will reveal more relevant approaches for their prevention and treatment.

Approach

What metabolic traits, characteristic of T2D, are causally associated with specific cancers?

We use a technique in genetic epidemiology called Mendelian randomisation (MR) to determine which metabolic traits characteristic of T2D are causally associated with site-specific cancer. Causal traits are prioritised for subsequent mechanistic investigation in the laboratory. This approach provides a means to bypass difficulties in associating T2D with specific cancers that result from T2D being a heterogeneous disease composed of many metabolic traits with the contribution of traits varying from person to person. By first understanding the components of the T2D metabolic profile and testing their association with specific cancers this problem of heterogeneity is reduced.

Do the metabolic traits characteristic of T2D promote carcinogenesis by inducing reprogramming of metabolic pathways within tumour cells?

We focus on two cancer types where the existing evidence (including large systematic reviews and meta analyses) for T2D being a risk factor is compelling: colorectal cancer and pancreatic cancer. To characterise the effect of metabolic traits on carcinogenesis will use three approaches: (i) Determine the impact of the metabolic trait on tumour cell phenotype. (ii) Determine the impact of the metabolic trait on tumour cell metabolism, and (iii) target the metabolic pathways altered by the presence of the trait with the aim to reverse the effect of the trait on the phenotype. To do this we use a range of techniques to assess tumour cell phenotype, but critical to our work is the use of Stable Isotope Tracer Analysis (GCMS) and extracellular flux analysis to measure cancer cell metabolism.

Impact

Normal approaches to cancer prevention and therapy may not be appropriate or optimal for people with T2D. To enable effective ways to screen for and to prevent and treat the cancers that develop in people with T2D we need to understand what is it about the characteristics of T2D that causes specific cancers to develop.