Study provides new insights into breast cancer metastasis

Fred Hutchinson Cancer Research CenterFeb 2 2016

It has long been thought that cancer metastasizes, or spreads, when a single cancer cell escapes from the original tumor, travels through the bloodstream and sets up shop in distant organs. However, a growing body of evidence suggests that these bad actors don't travel alone; instead they migrate through the body in cellular clusters, like gangs.

A new study by researchers at Fred Hutchinson Cancer Research Center and Johns Hopkins Medical Institute, published in PNAS Early Edition, confirmed that clusters of cancer cells indeed travel together throughout all stages of metastasis. The study also identified the molecular signatures unique to these highly aggressive, roaming tumor clumps, such as the fact that each are led by a gang member that's fueled by a type of cellular kryptonite: a highly expressed protein called keratin 14.

Ultimately, the findings may not only provide new insights into metastasis but also may point to potential drug targets to prevent or slow the deadly process, according to first and co-corresponding author Dr. Kevin Cheung, an assistant member of the Public Health Sciences Division at Fred Hutch. He began the research while working as a postdoctoral researcher and medical oncology fellow in the laboratory of Dr. Andrew Ewald, an associate professor in the Department of Cell Biology at Johns Hopkins, who is co-corresponding and senior author of the paper.

For the study, the researchers relied on a mouse model of breast cancer that spontaneously migrated to the lungs. Using a multicolor lineage tracing assay, they found that cancer cells not only travel together from the beginning to the end of their journey throughout the body, but they need to stick together to survive.

"It's a team game the whole way through," Cheung said. "This gang of thugs breaks off at the primary site, gets into the bloodstream and then sets up shop in distant organs." Cheung and colleagues also found that by breaking up the gangs into individual cells, they died. "Gangs have a much better ability to metastasize than single cells," he said.

Through RNA sequencing to understand which genes were expressed in these cells, the researchers also found that the gangs had changes in the expression of genes encoding for three different protein complexes:
•Higher expression of desmosome genes, which could allow the cells to easily stick to each other. "Think of it as a molecular rivet," Cheung said.
•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.
Further work is needed to directly test the consequences of these genetic changes, Cheung said. We need to do more studies to test these hypotheses and, ultimately, push these findings forward to develop new therapies for metastatic breast cancer.

"Of all stages of breast cancer, metastasis remains the hardest to treat," he continued. "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 Metastatic Breast Cancer Network, the number of people living with metastatic breast cancer in the U.S. is estimated to be more than 155,000. About 6 to 10 percent of new breast cancer cases are initially diagnosed at Stage 4, and an estimated 20 to 30 percent of all breast cancer cases will become metastatic. About 40,000 people die of metastatic breast cancer each year in the U.S., and late-stage breast cancer receives less than 5 percent of research funding compared to all cancers combined.