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Cancer clone maps provide direction on breast cancer metastasis

There are around 55,900 new breast cancer cases in the UK every year – more than 150 cases every day. Overall, the five-year survival rate is relatively good at around 88.3%. But, when breast cancer spreads (or metastasizes) to other parts of the body, the five-year survival rate drops to 20-30%.

A new technology, described in Nature, has been developed that pinpoints and traces which breast cancer cells metastasize and how this spread is dependent upon where the tumour starts in the breast. The pipeline was developed by a team from the Wellcome Sanger Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI), the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), the Science for Life Laboratory in Sweden, and several other collaborators.

Track and trace tumour trajectory

Cancer arises when cells gain genetic mutations that allow them to grow in a dysregulated and uncontrollable way. The mass that forms is a mosaic of cells, where each cell can have distinct genetic mutations. These are called cancer subclones.

Researchers used eight samples from two breast cancer patients in the study. The samples, which were large pieces of tissue sections, represented the main stages of early cancer progression: ductal carcinoma in situ, invasive cancer and lymph node metastasis. Scientists were able to reconstruct the spread of the clones by using a fluorescence microscopy-based workflow. They identified which cells caused metastasis and how tumour growth was affected by location.

“We have created a system that combines computational and experimental techniques that allows us to map evolutionary cancer lineages in their natural habitat of human tissue,” said Artem Lomakin, first author from EMBL-EBI and the DKFZ. “While it has been previously possible to trace the lineage of cancer tumour cells in an experimental setup, this is the first time that multiple lineages were traced in human tissues, giving a complete overview of breast cancer development in the body. Insights generated by our system were impossible to get before, especially at this scale.”

Location, location, location

The scientists developed a genetic clone mapping workflow using base-specific in situ sequencing (BaSISS) (figure 1). The technology genetically and physically mapped out clones within the cancer. Different mutations were targeted using thousands of fluorescent DNA-base specific probes. The signals were then detected using fluorescence microscopy. Mathematical modelling integrated the signals to produce cancer clone maps.

The scientists also aligned the cancer clone maps to information from spatially resolved single-cell transcriptomics and immunohistochemistry stains. This allowed further characterisation of the spatial phenotype and a deeper understanding of how genetic information links to phenotypic changes in a tumour.

Figure 1: BaSISS workflow. 1, Mutation specific probes were designed and tissue samples were sectioned. 2, Transcripts were detected using the probes. Amplified probes were detected using fluorescence microscopy. 3, Mathematical modelling of the signals from the probes generated the clone maps. 4, Clone maps were aligned to spatially resolved single-cell transcriptomics data and immunohistochemistry stains. Source: published in Nature.

The team found that there were variations in the stromal and immune cell types that surrounded cancer clones that originated from the same patient but were found in different parts of the breast tissue. This meant that cancer clones behaved differently depending on where they originated in the breast. Therefore, the study allowed researchers to see for the first time how the environment affects cancer evolution.

“An important insight from our research is that it may not be the genetic changes alone that are the reason that the cancer cells survive and spread; it could also be where they are,” said Professor Mats Nilsson, co-senior author from the Science for Life Laboratory at Stockholm University. “This adds an additional layer of complexity as well as new potential ways to target the disease. It may also offer explanations about why some treatments only work in some individuals, even if they have similar mutations to others, as the tumours are found in different areas of the breast.”

Watch this space

The application of spatial genomic approaches is likely to have significant implications for cancer treatment. The technology would allow tumours to be visualised in the context of the immune system and the surrounding microenvironment.

Dr Lucy Yates, co-senior author from the Wellcome Sanger Institute said, “To fully understand and therefore treat breast cancer, we need to be able to see the entire picture of how the cancer interacts in the body, with the cells around it, and with the immune system. This new technology combines multiple techniques and expertise to do this, bringing together different approaches to give a complete view of cancer that has not been previously possible.”

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