How cancer cells break free from tumors

Although tumor metastasis causes about 90 percent of cancer deaths, the exact mechanism that allows cancer cells to spread from one part of the body to another is not well understood. One key question is how tumor cells detach from the structural elements that normally hold tissues in place, then reattach themselves in a new site.

A new study from MIT cancer researchers reveals some of the cellular adhesion molecules that are critical to this process. The findings, published Oct. 9 in Nature Communications, offer potential new cancer drug targets, says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, and leader of the research team.

“As cancer cells become more metastatic, there can be a loss of adhesion to normal tissue structures. Then, as they become more aggressive, they gain the ability to stick to, and grow on, molecules that are not normally found in healthy tissues but are found in sites of tumor metastases,” says Bhatia, who is also a member of the David H. Koch Institute for Integrative Cancer Research at MIT. “If we can prevent them from growing at these new sites, we may be able to interfere with metastatic disease.”

Lead author of the paper is Nathan Reticker-Flynn, a PhD student in Bhatia’s lab. Other authors are former students David Braga Malta and Mary Xu, postdocs Monte Winslow and John Lamar, and research scientist Gregory Underhill. In addition, Richard Hynes, the D.K. Ludwig Professor of Biology and a member of the Koch Institute, and Tyler Jacks, director of the Koch Institute, are contributing authors on this study.

Losing and gaining adhesion

Cells inside the human body are usually tethered to a structural support system known as the extracellular matrix, which also helps regulate cellular behavior. Proteins called integrins, located on cell surfaces, form the anchors that hold the cells in place. When cancer cells metastasize, these anchors let go.

In this study, the researchers compared the adhesion properties of four types of cancer cells, taken from mice genetically engineered to develop lung cancer: primary lung tumors that later metastasized, primary lung tumors that did not metastasize, metastatic tumors that migrated from the lungs to nearby lymph nodes, and metastatic tumors that travelled to more distant locations such as the liver.

Building on a system they first described in 2005, the scientists developed technology allowing them to expose each type of cell to about 800 different pairs of molecules found in the extracellular matrix. After depositing cells onto a microscope slide in tiny spots - each containing two different extracellular matrix proteins — the researchers could measure how well cells from each tumor type bound to the protein pairs.

The new technology is a huge step forward from current experimental methods for studying cellular adhesion, which are limited to much smaller numbers of cells and adhesion molecules, says Jan Pilch, an assistant professor at the University of Pittsburgh School of Medicine.