A leading-edge genetic technique that can track cell lineage has revealed much about how breast cancer spreads. It could also help explain why some breast cancers relapse after initially successful chemotherapy.

The name of the technique is cellular barcoding, and it allows scientists to assess the diversity of cell populations, such as in tumors. They can also use it to tag cells and follow their identical descendants, or clones. Researchers at the Walter and Eliza Hall Institute of Medical Research in Australia used the technique to carry out a detailed investigation of breast cancer spread at the cell level using human tumor tissue transplanted into mice. A study paper that now appears in the journal Nature Communications gives a detailed account of the investigation and its results.

According to the World Health Organization (WHO), breast cancer is the "most common cancer in women." It accounted for more than 508,000 deaths worldwide in 2011.

Tumors contain thousands of cell variants

The main cause of death in breast cancer is its ability to spread, or metastasize, from the primary, or "main," tumor to form tumors in other organs of the body. Those working in the field of cancer research describe metastasis as the "last frontier." A particular challenge they face is unraveling what happens to tumor cells as they grow and proliferate.

Breast cancer tumors comprise a diverse mix of thousands of cell variants with disparate characteristics and development paths. Some of these influence the cancer's ability to spread, while others have no effect. "This complexity," say the authors, "has direct bearing on our understanding of tumor evolution, metastasis, drug resistance, and the sampling of lesions from patients to identify the most useful therapeutic targets."

With the help of cellular barcoding, the team showed that of the thousands present in a tumor, only a handful of clones was responsible for metastasis. "The barcoding technique," notes first study author Dr. Delphine Merino, one of the leaders of the investigation, "enabled us to identify the clones that were able to get into the bloodstream and make their way into other organs where they would 'seed' new tumor growth."

Cellular barcoding traced cell lineage

Cellular barcoding allows scientists to trace the lineage of cells by placing unique genetic markers, or tags, on them. An important advantage of the technique is its ability to track large numbers of different cells and their descendants in parallel. Study co-author Dr. Shalin H. Naik, who co-led the recent investigation, helped develop the cellular barcoding method that they used in the study.

He explains that the new version allowed them to home in on the handful of cell variants driving metastasis. Having identified which of the thousands of clones were involved in breast cancer spread, he and his colleagues can now focus their efforts on finding ways to block them. Dr. Naik remarks, for instance, that they "are curious to understand what is unique about these particular clones that enables them to successfully spread, seed, and grow the cancer."

Investigating effects of chemotherapy

Prof. Jane E. Visvader, another study leader, explains that the scientists also used the new cellular barcoding technique to investigate the effects of chemotherapy on the clones. They used donated human tissue to develop mouse models of breast cancer tumors and treated them with cisplatin, a chemotherapy drug that doctors use to treat a wide range of cancers.

"While the treatment was able to shrink tumors and the size of individual clones," Prof. Visvader points out, "it did not kill them off completely. All the clones, including the nasty seeders, eventually grew again, accounting for cancer relapse," she adds, noting that they were able to observe this because cellular barcoding allowed them to tag and follow thousands of individual clones and observe their activity over time. She believes that the findings will help future researchers develop highly targeted treatments for breast cancer.

"Our study revealed that only a select few clones were actually responsible for the metastasis."

—Dr. Delphine Merino