The genomic cartographers drawing an atlas of breast cancer
Despite decades of research and significant advancements in treatment, breast cancer remains the leading cause of cancer death in women. In part, this is because breast cancer isn’t a homogeneous disease, but rather what can best be described as a collection of very different diseases, each of which evolves and interacts differently. New research being conducted by the CLONCELLBREAST (Clonal and cellular heterogeneity of breast cancer and its dynamic evolution with treatment) project, supported by the European Research Council, has redefined breast cancer as a constellation of distinct genomic entities. “One of the greatest challenges to treating breast cancer is that it is a heterogeneous group of 11 diseases, each of which is defined by its own unique genomic profile,” says Carlos Caldas, a professor of Cancer Medicine at the University of Cambridge and CLONCELLBREAST principal investigator. “To make things more complex, each tumour is composed of clones, the evolution of which impacts metastasis and resistance to therapy.”
Understanding integrative clusters
Having identified the 11 distinct genomic entities of breast cancer, Caldas and his research team turned their attention to unravelling the clonal and cellular heterogeneity of the disease and its dynamic evolution with treatment. “Our goal was to define intra-tumour heterogeneity in tumours that have been classified into one of the 11 genomic subtypes, which we call integrative clusters,” explains Caldas. However, doing so was easier said than done. According to Caldas, because the tissues being studied were frozen at cryogenic temperatures, researchers were unable to isolate single cells. Instead, they had to develop a workaround, which in this case involved optimising protocols for single nucleus DNA and RNA sequencing. Now that they could profile the frozen tissues, researchers were able to confirm that tumours within each of the 11 integrative clusters have prototypical intra-tumour heterogeneity at the genomic, functional and cellular levels. Caldas explains this means that malignant cells are not a single clone but a family of clones that can be characterised at the single cell level using shallow, whole genome sequencing. It also means these cells are a constellation of malignant cell phenotypes that can be characterised at the single cell level using RNA sequencing. “Profiling the tumour microenvironment at the single cell level and cataloguing stromal cells and immune cells has given us a unique view of breast cancers with profound diagnostic and therapeutic implications,” adds Caldas.
A single cell atlas of breast cancers
Having characterised intra-tumour heterogeneity at an unprecedented scale, researchers used the collected data to create a single cell atlas of breast cancers. “Representing the full spectrum of the diseases, including tumours from all 11 integrative clusters, this atlas is the first of its kind,” notes Caldas. “The single cell atlas of breast cancer will significantly advance our understanding of tumour biology, including dormancy and metastases, and will help unravel drug resistance and why only a very small fraction of breast cancers respond to immunotherapy.” In addition to the atlas, the project has already published three papers in ‘Nature Communications’, with several more to come. Once the project is complete, all collected data will be made available to the research community via the EMBL-EBI portal.
Keywords
CLONCELLBREAST, breast cancer, tumour biology, cancer, genomic, metastasis, integrative clusters, genome sequencing, immunotherapy
