More than 90% of cancer deaths in America are attributable to metastasis, when cancer spreads from its original site to other parts of the body. Researchers at the Johns Hopkins Kimmel Cancer Center are studying the mechanics of breast cancer metastasis in pursuit of new therapeutic interventions.
It's potentially lifesaving work made possible by funding from the National Institutes of Health.
"The NIH is by far the largest funder of cancer research in the United States," explains Andrew Ewald, professor and director of the Department of Cell Biology and director of the Johns Hopkins Giovanis Institute. "And so what they're able to do is act at a scale and for a duration that is just qualitatively different from any other funder. They're able to commit to an idea and see it through over years. There are many options for small investments to catalyze research ideas, but all of those mechanisms depend on mature projects being able to win funding from the NIH to sustain that project for long periods of time."
This project has been ongoing since 2008, and thanks to the NIH, Ewald and other Johns Hopkins researchers have made significant strides in understanding what biological mechanisms allow a cancer cell from one part of the body to successfully grow in another part.
Their most recent breakthrough occurred last year; in an effort to better determine which cells are closest to breast cancer cells, the Johns Hopkins scientists analyzed primary and metastatic breast cancer tissue samples from 24 people who died from breast cancer and who donated their tissues to Johns Hopkins researchers through a rapid autopsy program. Other scientists have mapped cells in such tissues, but the Johns Hopkins researchers say their study focused not on what surrounds an average cancer cell, but what is closest to those cancer cells that are most likely to spread.
Ewald and former postdoctoral fellow Eloïse Grasset, now at the National Centre for Scientific Research in France, previously identified the biomarker signature common to breast cancer cells that are likely to spread, or metastasize.
The researchers used 36 such biomarkers to pinpoint metastasis-initiating cells and other "signatures" to identify cells next to them—those that were up close (within about 10 to 20 microns), others about three to four cells out, and cells further away.
"What popped out at us, among immune system cells, was a subset of macrophages very close to or touching metastasis-initiating cells in the primary and metastatic tissue samples," says Kimmel Cancer Center oncologist and imaging expert Won Jin Ho, an assistant professor of oncology and director of the Mass Cytometry Facility at Johns Hopkins. "The macrophage subsets are a minority—about 1%–5%—of the cells present in the tumor."
The research team confirmed the presence of key macrophage subsets in another set of more than 100 breast cancer samples from a tumor bank published in a previous study, showing that such distinct macrophage subtypes are, indeed, components of the breast cancer microenvironment.
A type of white blood cell, macrophages can swallow and destroy "foreign" cells on their own, but also can recruit other immune system cells to fight off cells they identify as foreign to the body. Ho says that other studies have shown that tumors with many macrophages may indicate a poorer prognosis and less response to immunotherapy.
The finding could provide a new biological target for immunotherapies designed to destroy spreading cancer cells.
"As discovery-based scientists, we're looking for ways to change the immune system's spatial organization in the microenvironment surrounding cancer cells," Ewald says. "Eventually, we could develop biologic therapies to change how neighborhoods of cancer cells are organized."
Other researchers involved in the study are Atul Deshpande, Jae Lee, Yeonju Cho, Sarah Shin, Erin Coyne, Alexei Hernandez, Xuan Yuan, Zhehao Zhang, and Ashley Cimino-Mathews from Johns Hopkins.
