Scientists have developed a novel drug combination that makes invasive breast cancer cells transform into fat cells. The treatment prevented metastasis in mice.

Metastasis is the process through which cancer cells escape from primary tumors and grow new tumors, or metastases, in other parts of the body. It is the leading cause of death from cancer. An enabler of metastasis is the innate ability of cancer cells to take on the properties of other cell types. This "plasticity" allows them to transform from anchored cells into ones that can travel and invade other tissues.

Now, researchers at the University of Basel in Switzerland have found a way to use cell plasticity to stop metastasis in breast cancer. Instead of allowing the breast cancer cells to grow and migrate, they forced them to become fat cells that do not divide or travel. The journal Cancer Cell has recently published a paper about the research.

"In future," says senior study author Gerhard Christofori, who is a professor in the Department of Biomedicine, "this innovative therapeutic approach could be used in combination with conventional chemotherapy to suppress both primary tumor growth and the formation of deadly metastases."

Metastasis and cell plasticity

The complex process of metastasis comprises a sequence of steps that scientists often refer to as the "metastatic cascade." There are three main stages in the cascade: invasion, in which cancer cells detach from the primary tumor environment; intravasation, in which the cells enter blood vessels; and extravasation, in which they exit blood vessels.

Cancer cells take on different properties to complete each of these stages. In the first stage, for example, the cells lose their ability to stick to each other and their surroundings, allowing them to detach from the primary tumor tissue.

In the case of breast cancer, and other cancers that arise in the epithelium, doctors refer to the change that the tumor cells undergo during metastasis as the epithelial-mesenchymal transition (EMT). EMT also occurs in developing embryos. In cancer, however, EMT does not help to form new organs but new tumors.

Breast cancer cells take properties of fat cells

Among women, cancer of the breast is the most common cancer and is responsible for most deaths that doctors relate to the disease. Estimates from the World Health Organization (WHO) suggest that around 2.1 million women receive a diagnosis of breast cancer every year. These also suggest that 627,000 women died of the disease in 2018. The vast majority of breast cancer deaths are due to cancer spreading locally and setting up new tumors in other parts of the body.

Prof. Christofori and his team investigated the EMT molecular processes that enhance plasticity in breast cancer cells to enable metastasis. Using human cells and mouse models, they found that they could exploit this plasticity and force the cancer cells to turn into fat cells with a particular combination of compounds. The newly-formed fat cells were very similar to normal fat cells and were unable to divide and proliferate. The authors note that this led to "repression of primary tumor invasion and metastasis formation."

The compounds in the combination were the diabetes drug rosiglitazone and trametinib, a drug that can stop the growth and spread of tumor cells. The researchers also point out that, in many respects, because of their high plasticity, breast cancer cells resemble stem cells. Exploring these similarities could be a fruitful avenue for further research.