Breakaway breast cancer cells can travel to the brain: Scientists are tracking their path to block entry

One of the most puzzling—and devastating—aspects of cancer is its potentially lethal wanderlust, the spread of the disease from a primary tumor to a new and distant site.

The process is formally called metastasis, which at its most basic is recognized as cancer cells on-the-move. Having broken away from a primary tumour these malignant migrants hitch a ride aboard the blood or lymphatic systems to seed new tumours. As countless studies have shown, certain forms of cancer have preferential destinies.

Among the people who develop metastatic breast cancer, about 10% to 15% with stage IV disease have brain metastases. The risk of brain metastasis is usually highest for those with more aggressive subtypes of breast cancer, such as HER2-positive or triple negative breast cancer according to Breastcancer.org.

Scientists are studying the development of brain metastases in patients with breast cancer. Knowing how these cancer cells make their way to the brain helps lay the groundwork for interventions that block tumour cells' well-beaten path. Blocking the cells from a target tissue is vital because metastatic cancer is inevitably worse in terms of its aggression and harder to fight than a primary tumour.

Writing in Science Translational Medicine, researchers have demonstrated how proteins called connexins orchestrate the spread of metastatic breast cancer to the brain—an event that drastically worsens patients' prognoses. In the laboratory, the research team conducted in vitro and in vivo studies to show that connexins and the enzyme focal adhesion kinase—FAK—likely play a major role in the invasion of the brain by cancer cells. Connexins belong to a family of proteins that form intercellular membrane channels permitting the flow of ions and small molecules between adjacent cells.

This research  work illuminated how connexin-mediated FAK enzyme activation promoted cell adhesion, tumor-astrocyte interaction, and tumour survival within the brain's parenchyma. The parenchyma is the functional tissue in the brain comprised of two types of cells involved in cognition and controlling the body. The remaining brain tissue, known as stroma, is the organ's structural tissue.

The scientists found that connexins activated by the enzyme FAK, can in turn, stimulate signaling pathways that sustain breast cancer cells in brain tissue. The team proved in three different mouse models that connexin proteins drive the spread of breast cancer cells to the brain. When the mice were treated with inhibitors of FAK, an approach already being tested in human clinical trials, the growth of metastatic breast cancer cells was suppressed in the brain.

They suggest FAK inhibitors are likely the most promising strategy for clinical translation at the moment because connexin inhibitors are still unavailable for humans, and the side-effect profile has yet to be established.

Girieca Lorusso et al, Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation, Science Translational Medicine (2022). DOI: 10.1126/scitranslmed.aax8933