Tumours are genetically diverse with different mutations arising at different times throughout growth and development.

Many models have tried to explain how genetic heterogeneity arises and what impact these alterations have on tumour growth.

In a new article published in Nature Communications, Moffitt Cancer Center researchers show how the location of the tumour and spatial constraints put on it by the surrounding tissue architecture impact genetic heterogeneity of tumours.

Genetic differences are apparent among tumours from different patients, as well as within different regions of the same tumour of an individual patient.

Some of these mutations may benefit the tumour and become selected for, such as mutations that allow the tumour to grow faster and spread to other sites.

This type of tumour evolution is known as Darwinian evolution. Alternatively, other cellular mutations may have no immediate impact on the tumour but still accumulate over time, known as neutral evolution.

Researchers in Moffitt's Center of Excellence for Evolutionary Therapy wanted to determine how the surrounding tissue architecture impacts these different types of tumour evolution patterns and genetic heterogeneity.

The team used mathematical modelling to determine how spatial constraints impact tumour evolution with a focus on the three-dimensional architecture of ductal carcinoma of the breast.

They used a well-studied model of tumour evolution and altered variables related to spatial constraints and cell mixing and demonstrated that the surrounding tissue architecture greatly affects the genetic heterogeneity of tumours over time.

For example, the ductal network of breast tissue is similar to the trunk and branches of a tree.

A tumour that forms within the wider region of the base of the duct has less spatial constraints placed on it compared to a tumour that initially forms in the smaller ductal branches.

As a result, a tumour near the base tends to acquire mutations over an extended time and will have more genetic heterogeneity due to neutral evolution.

On the other hand, a tumour within the smaller ductal regions tends to undergo accelerated genetic changes that result in one mutation becoming dominant due to Darwinian evolution, - also known as clonal sweep.

"Two otherwise identical tumours may realise dramatic differences in fitness depending on constraints imposed by tissue architecture," said Sandy Anderson, Ph.D., study author and director of the Center of Excellence for Evolutionary Therapy at Moffitt.

"On the cell scale, any given subclone may have a selective advantage. Yet, the effective outcome of this subclonal advantage depends on the surrounding competitive context of that cell. In other words, cell-specific phenotypic behaviour can be 'overridden' by the tissue architecture, allowing the tumour to realise increased fitness."

The study sheds light on the important role that tumour location has in the development and progression of cancer and helps explain the wide variety of mutational patterns observed among different patients.

"Our approach adds clarity to the debate of neutral tumour evolution by exploring a key mechanism behind both interpatient and intratumoural tumour heterogeneity: competition for space," said Jeffrey West, Ph.D., study co-author and postdoctoral fellow in the Integrated Mathematical Oncology Department at Moffitt.

Source and image: H. Lee Moffitt Cancer Center & Research Institute