Deciphering and targeting cancer metabolism using executable models

点击翻译按钮获取中文摘要

The progression of cancer is driven by mutations and errors in the cell that promote the "hallmarks of cancer". These are a set of distinct behaviours that cells in tumours possess, enabling the survival and growth of the cancer. A longstanding observation in cancer cells is the Warburg effect; the switch away from oxidative phosphorylation to anaerobic glycolysis. Recent evidence has shown that metabolic reprogramming- large scale modification of how the cells process energy- is achieved by mutations in oncogenes including KRAS. This enables cancer cell survival in the tumour. Furthermore mutations in individual metabolic enzymes, such as fumarate hydratase, can affect a transition from epithelial to a mesenchymal morphology. Both the links between individual metabolites and cell behaviour, and the role of the metabolic network in cancer development however remains unclear. Knowledge of both of these are necessary to interpret metabolic changes in cancer and to identify new drug targets that are robust to network effects.Computational modelling offers the opportunity to formalise the relationships between elements in the network and to address this issue. However, conventional approaches based on ordinary differential equations (ODEs) and flux balance analysis (FBA) are not suitable. ODE models require precise physico-chemical parameters that are not available for human metabolism. FBA does not have this requirement but is not capable of modelling the accumulation of metabolites that can occur in response to mutation. I propose to use an "executable" modelling approach to construct models of the metabolic network and link them to cellular behaviour. Executable modelling approaches do not require detailed physical parameters, and can model accumulation events. They have the further advantage that they are amenable to a class of model analysis known as formal verification. Here mathematical proofs are used to offer guarantees of cell properties that are encoded in formal logic. These guarantees can apply over all possible states of the system and so offer a uniquely powerful way to test model correctness. This is particularly useful for highly robust systems such as the metabolic network, but also in taking account of rare events. This latter issue is particularly important when considering how rare events determine the development of cancer. Model building will be guided by the use of machine learning approaches (t-SNE, decision forests) to address publicly available expression data and metabolomic datasets shared with us by AstraZeneca. Finally, these models will be used to make novel predictions about the metabolism can change cell phenotype. The development of these models will allow us to understand how metabolic networks drive cancer progression and help us identify novel oncogenes and drug targets.