A new commentary, published in Nature Genetics discusses integrative approach to study cancer heterogeneity. Heterogeneity is the single most important factor driving cancer progression and treatment failure, yet little is understood about how and when this heterogeneity arises. A new study shows that colorectal cancers acquire their dominant mutations early in development and that subsequent mutations, even if they confer greater fitness, are unlikely to sweep through the tumour.
Lee Moffitt Cancer Center & Research Institute researchers are using integrative approaches to study cancer by combining mathematical and computational modeling with experimental and clinical data. The use of integrative approaches enables scientists to study and model cancer progression in a manner that conventional experimental systems are unable to do.
Alexander Anderson, PhD, chair of the Department of Integrated Mathematical Oncology and Mark Robertson-Tessi, an applied research scientist in the same department, recently published a commentary on an integrative approach used to study cancer heterogeneity.
Cancer is a heterogeneous disease, with genetic variations occurring between different types of tumours and different patients. More importantly, heterogeneity also exists among the cells of a single tumour. This heterogeneity makes treating cancer extremely difficult and can also lead to resistance to therapeutic agents.
Anderson and Robertson-Tessi explained that in order to develop better therapeutic approaches, it is important for scientists to identify these variations and how they lead to tumour growth and invasion. They described a new theory called the "Big Bang" model of cancer heterogeneity, developed by researchers from the University of Southern California.
The traditional model of tumour heterogeneity suggests that sequential mutations over time lead to the emergence of fitter cells that continue to grow and take over the tumour – called the clonal selection model. Contrary, the Big Bang model suggests that for some tumours, mutations occur early during development when tumours are smaller. This type of heterogeneity is common in tumours that are not limited by space and have a lot of room to grow and expand, as exemplified by colorectal cancer.
According to the Moffitt scientists, this paradigm shift may have significant implications for treatments for cancer that develop similar to colorectal cancer. Following cancer therapy, the dominant cells may die first, and other cells that were originally not as fit may find themselves better able to compete for necessary space and nutrients and continue to grow and take over the tumour.
"Understanding how heterogeneity changes with treatment is key to controlling the emergence of aggressive and resistant clones following therapy," explained Anderson. However, current therapeutic approaches that treat a tumour until resistance develops, ignore the fact that tumours can change during treatment.
The integrated approaches being developed and used at Moffitt are instrumental for the continued advancement in the understanding of cancer progression and the development of novel cancer therapies.
Robertson-Tessi M, Anderson ARA. Big Bang and context-driven collapse. Nature Genetics 2015; 47, 196–197. doi:10.1038/ng.3231