Molecular microscopy maps growth of breast cancer in new detail
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New technology that identifies which populations of breast cancer cells are likely to drive invasion and metastasis has revealed that the location of cancer cells may be as essential to tumor growth as mutations.
The technology was created by a collaborative team from Wellcome Sanger Institute, European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI), German Cancer Research Center and Science for Life Laboratory.
A proof-of-concept study of the tool, published in Nature, revealed its potential to map tumor development by combining the cancer cells’ genetic information with that of nearby cell types and their interactions. This approach could be used to determine how treatments affect cancer at the genetic level and also monitor how tumors interact with the immune system.
“The field of spatial omics has been developing quite rapidly in recent years,” lead author Artem Lomakin, a predoctoral fellow from EMBL-EBI and German Cancer Research Center, told Healio. “There have already been technologies to reliably map some of the proteomics and transciptomics in space. However, to trace the genotype, to look at the evolution of the cancer cells, you need to be able to trace the genotypes in space, as well. This is very challenging, primarily because there are few copies of DNA in the cell in comparison to proteins and RNA.”
Evaluating clonal populations
As a tumor develops over time, it differentiates into a patchwork of cells called cancer clones, each with a distinct set of mutations. The genetic differences mean the cells may react differently to treatment, with some cells potentially becoming treatment-resistant and others spreading throughout the body. The success of the cancer clone is affected by the surrounding cells and the individual’s immune system. For this reason, understanding the environment of a cancer cell and its emerging mutations can provide insight into tumor evolution.
The researchers developed a genetic clone-mapping approach focused on base-specific in situ sequencing (BaSISS) technology. They obtained quantitative maps of multiple genetic clones in eight tissue blocks from two patients with multifocal breast cancer comprising the main histologic stages of early cancer progression: ductal carcinoma in situ, invasive cancer and lymph node metastasis.
“We used some of the established technologies, like in situ sequencing, combined with the advanced computational inference techniques, to locate those clonal populations,” Lomakin said. “What is new is to be able to observe genetic composition and the environment — the conditions in which those cancer cells grow — simultaneously because the environment of the tissue, the structure, the chemicals that happen to be in those locations, are all forming this selective pressure on the subpopulation of tumor cells. This dictates how they will evolve in the future and shape the evolution of cancer.”
Adapting to the tumor environment
The researchers found distinct and unanticipated patterns of clone growth across multiple stages of breast cancer development. They also found differences in the behaviors of these genetic clones depending on their location in the breast.
“We found that the different subclones and evolutional lineages often inhabit completely different ecological niches within the tumor. One example is metastasis in the lymph node,” Lomakin said. “We see that there are two clones — two very different evolutional lineages — one of which grows in huge lumps that have a very classical appearance of necrotic cores. Other groups of cells live in a peculiar, very disseminated way in what looks like small spheres around the immune cells.”
Lomakin said although the researchers do not yet understand the reasons for this different behavior, it is a good indication that these groups of cells managed to adapt to very different living conditions compared with the other evolutionary branch of cells.
“We saw this pattern in every sample that we looked at,” he said. “There is a clear linkage between the environment in which cancer cells live and their genotype.”
Containing the evolution
The information gleaned from this tool could be used to guide development of treatments that inhibit or prevent tumor growth by influencing the environment around the tumor. Additionally, researchers could use this technology to evaluate how new treatments impact cancer and interact with the immune system.
“To beat cancer, we need to understand how and why it evolves one way or the other,” Lomakin said. “With this technology, we have a better understanding of the conditions in which the cancer evolves, and therefore, by looking at more and more tissue samples, we will hopefully find the patterns. We will learn what conditions are dangers so that we can target them and contain the evolution.”
Lomakin discussed one case in which evolutional lineages diverged during the patient’s adolescence. Some of the lineages became aggressive and developed into a cancer, whereas others remained within the ductal system of the breast.
“They still look precancerous, but throughout the decades, they did not progress further into invasion,” he said. “That means that there is something there that should be able to tell us why one lineage of cancer cells might progress and ultimately kill people, while others remain in the tissue and don’t impose much danger on a human life.”
For more information:
Artem Lomakin can be reached at EMBL-EBI, Wellcome Genome Campus, Hinxston, Cambridgeshire, CB10 1SD, United Kingdom; email: artem.lomakin@dkfz-heidelberg.de.
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