Researchers have discovered that the two most common forms of lung cancer metabolise nutrients differently, revealing new vulnerabilities that could be exploited in future treatment for patients.
When cells become cancerous, they change their metabolism in order to grow rapidly and spread throughout the body. Previous studies suggested that the major subtypes of lung cancer differ metabolically, but exactly how they differ was unknown.
In a collaboration led by the Francis Crick Institute and the University of Kentucky, scientists have worked out how adenocarcinomas and squamous cell carcinomas in human patients metabolise nutrients. These are the two most common forms of lung cancer; around 40% of all lung cancers are adenocarcinomas while 30% are squamous cell carcinomas.
The research, published in the British Journal of Cancer, reveals that squamous cell carcinomas break down nutrients in a different way to adenocarcinomas and that it is linked to specific genetic events.
“Understanding how these cancers process nutrients could help us to develop new targeted treatments and lifestyle interventions," says Mariia Yuneva, group leader at the Crick and senior author of the study. "Our findings may also help to explain why these cancers respond to existing treatments in different ways."
In vivo systems
In order to study how tumours metabolise nutrients in the body, the team recruited lung cancer patients due to undergo surgery to remove their tumours. After 8 hours of fasting, and shortly before their surgery, half of the patients were injected with a non-radioactive labelled form of glucose, that would be taken up and metabolised by tumour cells.
The tumours removed during surgery were instantly frozen using liquid nitrogen, or sliced and kept in culture, and later analysed for metabolites and metabolic pathway activities. This analysis combined with gene analysis of publicly-available genetic data revealed a metabolic signature separating squamous cell carcinomas from adenocarcinomas. This metabolic signature also strongly correlated with higher levels of genes regulated by Notch signalling pathway, which can cause tumours to develop.
To further investigate the relationship between the Notch signalling pathway and metabolism in lung cancer, the team genetically modified mice to over-express NOTCH1, one of key Notch genes in lung cancers. The tumours that developed in the animals’ lungs had the same metabolic signature as the patients, reinforcing the link between these cancer-inducing pathways and metabolism.
Interestingly these findings could not be replicated in established cancer cell lines observed in the lab, emphasizing the importance of studying lung cancer metabolism in living animals and people.