Targeting cancer cells' escape vehicles to stop tumor metastasis

Many cancer deaths are the result of metastasis, the process in which tumor cells grow and migrate to other sites within the body. Tiny packages called "exosomes" are known as escape vehicles for proteins and RNAs that promote such progression. What if we could stop tumor growth by putting a brake on exosome production? Scientists led by the University of Wisconsin-Madison have found a way through a protein.

The researchers discovered that exosome release is dependent on a protein called Munc13-4. Because Munc13-4 binds to calcium, which could stimulate exosome secretion, the team managed to stop exosome production in breast cancer cells after they removed the protein or replaced it with a revised version unable to bind to calcium.

Their findings, published in the Journal of Cell Biology, open up new possibilities for therapeutic approach against cancer. "Overall, we think that increased expression of Munc13-4, combined with elevated calcium levels, drives enhanced exosome release by highly aggressive cancer cells, and that Munc13-4 is a potential target for therapeutic intervention," said professor and co-author Thomas F.J. Martin in a statement.

Exosomes exist in bodily fluids and play an important role in intercellular communication, because they can release their contents into other cells, thereby affecting their function. Cancer cells produce them in large numbers. Exosomes can transfer oncogenes to other cells, help cancer cells change their original surroundings and establish a foothold in other tissues, and carry signaling factors that suppress the immune response against tumors.

The study’s lead author, Scott W. Messenger, had previously found that Munc13-4 co-promotes the development of multivesicular bodies, which release exosomes when fused with the plasma membrane. There’s an enzyme called MT1-MMP among the proteins and RNAs that tumor-derived exosomes carry. By degrading the extracellular matrix around cancer cells, MT1-MMP helps cancer cells disperse from the site of origin to distant locations.

When Martin and colleagues removed Munc13-4, the exosomes that contained MT1-MMP from breast cancer cells diminished and stopped destroying the extracellular matrix, they reported.

Oncology researchers around the world are searching for new ways to halt metastasis in many tumor types. Last summer, University of Michigan scientists sequenced both DNA and RNA from 500 patients with metastatic tumors and found that 75% had "actionable" mutations, or irregularities that could be targeted with drugs that are already on the market. A team at the University of Chicago is examining a chemical messenger in lymphatic vessels called vascular endothelial growth factor-C, which they believe helps boost the effectiveness of checkpoint inhibitors used in immuno-oncology. And MIT researchers are looking at a combination of gene therapy and chemotherapy as a way of blocking metastasis in breast cancer.

The University of Wisconsin-Madison researchers believe their discoveries could be useful beyond breast cancer. They also found that lung and pancreatic cancer cells increase their Munc13-4 levels and disperse more exosomes as they become more aggressive.