Investigating genomic instability in cancer
Cancer drug resistance is a widespread problem. One recent discovery linking drug resistance, recurrence of disease and death in non-small cell lung cancer is the variation in the number of copies of genomic regions – either within cells in the same tumour or different tumour regions in a patient. “Within a tumour, there will be copy-number changes that are observed in every cell,” explains Eva Grönroos, senior laboratory research scientist at the Francis Crick Institute(opens in new window). “The result is that not all cells within the tumour have an identical chromosome copy number, and have a different genetic make-up,” she adds. In the PROTEUS project, which was funded by the European Research Council(opens in new window) (ERC) and led by professor Charles Swanton(opens in new window), researchers sought to dive deeper into this discovery, developing lung cancer models that could help uncover the evolutionary patterns behind this genomic instability. “One of the insights gained in this project was that these changes are not completely random(opens in new window),” says Grönroos. “The same gains and losses are often observed within a specific tumour type, indicating cancer type-specific selection pressures shaping the tumour genome.”
Understanding the complex role of the immune system in fighting cancer
As part of the project, the researchers used a method known as ‘tumour barcoding’ to investigate the effect of potential tumour suppressors on tumour growth. Using mouse models and CRISPR/Cas9 gene editing technology to inactivate specific genes, the team showed that inactivation of some of these suspected suppressor genes resulted in very large tumours(opens in new window) – while others were involved in the initiation of the tumour. “During the course of this project, we and others have come to appreciate the complex role played by the immune system(opens in new window) with regards to tumour initiation and progression,” notes Swanton.
Implications for air pollution and lung cancer
For example, it has long been known that air pollution is associated with an increased incidence of lung cancer, but the PROTEUS project found new links between environmental pollutants and tumour growth. Using epidemiological data, mouse models and in vitro experiments, the team showed that air pollution promotes lung cancer(opens in new window) independently of genetic mutations. Their findings showed that exposure to pollutants activates the immune system, which releases pro-inflammatory signalling substances. These then act on pre-existing, mutated cells in the lung to promote tumorigenesis – one process of normal cells turning into tumours. PROTEUS findings suggest that the ‘initiator’(opens in new window) of a tumour is a pre-existing mutated cell carrying a cancerous mutation, which may be acquired with age. The tumour ‘promoter’, based on their studies, could be air pollution, which triggers an inflammatory response that accelerates tumour formation. “We believe that our work on air pollution and lung cancer has the widest implications of all our findings during this project,” says Grönroos.
Feeding into cancer therapeutics
Through their work on air pollution, inflammation and tumour promotion, the researchers hope to find new ways to prevent cancer initiation through the use of anti-inflammatory agents in high-risk populations, opening up a new field of molecular cancer prevention. The research will be pursued further through a new ERC grant. “Data from us and others have shown that the body is riddled with mutated cells that never form a cancer,” adds Grönroos. “Our current grant focuses on what factors might be involved in promoting the switch from a mutated, indolent cell to cancer.”
