Metabolic reprogramming is a hallmark of cancer that contributes to malignant transformation and tumour progression. In recent years, there has been growing interest in developing strategies to exploit the metabolic vulnerabilities of cancer cells for therapeutic gain. However, our ability to do this is dependent on a thorough understanding of the ways in which cancer cell metabolism is influenced by cell-intrinsic and cell-extrinsic factors.
Signalling networks downstream of oncogenes regulate cancer cell metabolism. Our recent studies have focused on the oncogenic transcriptional co-activator YAP. Aberrant activation of YAP is widespread in human cancers yet, there is little knowledge regarding mechanisms by which YAP drives tumourigenesis. We find that YAP overexpression induces de novo lipogenesis in vitro and in vivo via transcriptional upregulation of a critical effector of the oncogenic phosphoinositide 3-kinase (PI3K) pathway. Importantly, inhibition of key enzymes in the de novo lipogenesis pathway blocks the uncontrolled proliferation associated with YAP-driven transformation. Our data reveal a mechanism of crosstalk between two important oncogenic signalling pathways and reveal a metabolic vulnerability that can be targeted to disrupt oncogenic YAP activity.
A variety of factors in the tumour microenvironment also have a major impact on cancer cell metabolism. Our studies have focused on characterising metabolic reprogramming events triggered upon chemotherapy exposure. Using in vitro and in vivo metabolomic profiling, we find that chemotherapy exposure induces an increase in the abundance of pyrimidine nucleotides as a result of increased flux through the de novo pyrimidine synthesis pathway. We find that pharmacological inhibition of de novo pyrimidine synthesis sensitizes cancer cells to genotoxic chemotherapy agents by exacerbating DNA damage. Our studies provide pre-clinical evidence to demonstrate that adaptive reprograming of de novo pyrimidine synthesis represents a metabolic vulnerability that can be exploited to improve the anti-cancer activity of genotoxic chemotherapy agents for the treatment of TNBC.
Together these studies highlight the importance of understanding how intrinsic and extrinsic factors are integrated to influence cancer cell metabolism.