A new spatial technology, base-specific in situ sequencing (BaSISS), has mapped and tracked cells and the tissue environment of breast cancer tumors—offering insights into some of the molecular factors that drive cancer progression. The study uncovered which populations of breast cancer cells are responsible for the spread of the disease, and for the first time highlights the importance of the location of cancer cells in tumor growth.
The new study is published in Nature, in the article, “Spatial genomics maps the structure, nature and evolution of cancer clones.”
“Our research has created a tool that can trace which breast cancer cells go on to cause tumors in other parts of the body, and can help answer some of the big questions in cancer, such as why some cancer cells spread and some don’t,” said Lucy Yates, PhD, clinician scientist fellow at the Wellcome Sanger Institute. “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.”
The team developed a workflow to create detailed quantitative maps of genetic subclone composition across whole-tumor sections. The technology uses fluorescent molecular probes to interrogate cellular DNA and RNA and scan large pieces of tissue using fluorescence microscopy. They found that across multiple stages of breast cancer development there were specific, and often unexpected, patterns of clone growth and that genetic clones behave differently depending on where in the breast they started.
“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,” noted Artem Lomakin, a PhD student in the Gerstung lab at EMBL’s European Bioinformatics Institute (EMBL-EBI) and the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). “While it has been previously possible to trace the lineage of cancer tumor 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.”
More specifically, the authors wrote that “applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection.”
“Cancer is caused by genetic mutations in a cell and this research was the first time that we were able to use DNA base specific probes to target dozens of these mutations in a set of cancer cell clones. This innovative technique allowed us to accurately reconstruct the spread of these clones,” noted Mats Nilsson, PhD, professor at the Science for Life Laboratory at Stockholm University. “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. 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 tumors are found in different areas of the breast.”
In a case of ductal carcinoma in situ, they noted, “polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures.” Across the stages of ductal carcinoma in situ, “invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments.”
“Sequencing cancer tumors can give us a good understanding about the genetic diversity in a tumor. But the exciting thing about this technology is that for the first time, we can see how the environment shapes cancer evolution,” noted Moritz Gerstung, PhD, division head, DKFZ. “We were able to see which cancer clones progress to become more aggressive, and which don’t, and this will enable us to get a much better understanding of what the key steps are in tumor growth, and how we can lessen or prevent disease.”
In the future, it could be possible to develop therapies that could prevent or lessen the cancer’s ability to grow and spread, by influencing the environment around the tumor. In addition to this, researchers could use the newly developed tool to test how new treatments affect both the cancer and its interaction with the immune system, giving a complete picture of how therapies work and any possible side effects.