Cells Gang Up to Form Breast Cancer Metastases, Study Shows

Breast Cancer metastases

Kevin Cheung, MD

A team of researchers at both the Fred Hutchinson Cancer Research Center and Johns Hopkins Medical Institute have discovered that cancer metastization occurs through the migration of malignant cells in groups, rather than single cells, in a recent study.

The study, published inPNASEarly Edition,¹confirmed the possibility of cancerous cells traveling in groups through a person's bloodstream and infecting other organs. These group-based migrations are consistent throughout all stages of metastasis and all share a high expression of the protein keratin 14.

Kevin Cheung, MD, principal investigator at the Cheung Lab, Fred Hutchinson Cancer Research Center, and lead author on the study, said metastasis tend to be more successful when created utilizing a group of cancerous cells.

“It’s a team game the whole way through,” Cheung said in a press release from Fred Hutchinson Cancer Research Center.²“This gang of thugs breaks off at the primary site, gets into the bloodstream, and then sets up shop in distant organs. Gangs have a much better ability to metastasize than single cells." Cheung added that when the groups were broken up in transit, any straggler cells would die.

Researchers in the study employed a mouse model of breast cancer, where they observed the malignancy's migration to the lungs. Researchers used a multicolor lineage tracing assay to determine that the cancerous cells traveling from the original site to the lungs not only stuck together, but these groups were imperative to their survival.

In order to determine how the metastasis occurred, researchers used multicellular seeding. If a single color showed up in a metastasis, researchers would be able to conclude that it occurred from single-cell seeding. A multicolored metastasis would mean the distant malignancy was of a multicellular origin.

"We reasoned that if lung metastases arose exclusively from seeding of single disseminated tumor cells, then each lung metastasis should express only one color," said Cheung, in the study. "In contrast, multicellular seeding should be able to produce metastasis with both colors."

In the tests run on the 16 mouse models across 4 separate experiments, researchers found the lung metastasis were comprised of anywhere between 2 and >1000 cells from the original tumor.

According to Cheung, this finding is important due to the fact that breast cancer metastases is difficult to treat, and it is also significant for other cancer types that may metastasize to the breast.

"Of all stages of breast cancer, metastasis remains the hardest to treat,” he said. "If you think of this study as a roadmap, then the work in my laboratory is now directed at creating the battle plan to combat this challenge."

According to the press release, researchers utilized RNA sequencing to determine which genes were expressed in the metastatic cells and found the "gangs" had changes in certain gene expression for three of their different protein complexes.

• Higher expression of desmosome genes, which could allow the cells to easily stick to each other.
• Higher expression of hemi-desmosome genes, which could make gangs adept at grabbing on to their surrounding microenvironment—such as latching on to a vein near the liver.
• Lower expression of genes involved in antigen presentation that could allow the thugs to evade the body’s immune system—specifically, T cells.

In the study, Cheung states that the research team's data does not completely exclude single-cell seeding for metastasis, or transitions between single cell and multicellular metastasis.

"Our data do not exclude the possibility of transitions between single cell and multicellular organization in the mammary stroma before intravasation," he said.

"Future studies are needed to map the relative frequency of different single-cell and multicellular configurations and their molecular features across the entire mammary fat pad and in different cancer models."

Cheung closed by saying further work is needed to directly test the consequences of these genetic changes.

"We need to do more studies to test these hypotheses, and ultimately, push these findings forward to develop new therapies for metastatic breast cancer."

References

1. Chueng K, Padmanaban V, Silvestri V, Schipper K. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters.Proceedings of the National Academy of Sciences. 2016. http://www.pnas.org/lookup/doi/10.1073/pnas.1508541113. Accessed February 1, 2016.
2. Fred Hutch News Releases. Study reveals how cancer cells travel together, like ‘a gang of thugs’. 2016. Available at: http://www.fredhutch.org/en/news/releases.html. Accessed February 1, 2016.