Squeezing into tight spaces makes cancer cells more aggressive and helps them evade cell death, study finds eLife.

The results reveal how mechanical stress makes cancer cells more likely to spread or metastasize. Although metastasis is the cause of most cancer deaths, there is currently no cure available. However, the new findings may help scientists develop new approaches to treat or prevent metastasis.

It can be a squeeze for cancer cells to escape from their tumor or enter tiny blood vessels, called capillaries, to spread through the body. Cells must collapse and change shape to do this, in a process called confined migration. As they spread, cells must also avoid detection and destruction by the immune system.

“Mechanical stress can cause mutations in cancer cells, as well as an uncontrolled increase in cell number and greater tissue invasion,” says first author Deborah Fanfone, a postdoctoral fellow at the Lyon Cancer Research Center, France. “We wanted to know if the mechanical stress of confined migration makes cancer cells more likely to metastasize, and how this happens.”

To answer these questions, Fanfone and her colleagues forced human breast cancer cells through a membrane with tiny three-micrometer holes to simulate a confined migration environment. After just one pass through the membrane, they found that the cells became more motile and resistant to anoikis – a form of programmed cell death that occurs when cells detach from the surrounding web of proteins and other molecules that support them (the extracellular matrix). The cells were also able to escape destruction by natural killer immune cells.

Further experiments showed that increased expression of inhibitors of apoptosis (IAP) proteins increased the resistance of cancer cells to anoikis. Treating cancer cells with a new type of cancer drug called SMAC mimetic, which degrades IAPs, removed this protection.

The team then studied the behavior of breast cancer cells that had undergone confined migration when given to immunocompromised mice. They found that these mice developed more lung metastases than mice given breast cancer cells that had not been exposed to confined migration.

“By mimicking confined migration, we were able to explore its multifaceted effects on cancer aggressiveness,” says lead author Gabriel Ichim, who leads the Cancer Cell Death team at the Lyon Cancer Research Center. “We showed how the process boosts the survival of cancer cells and makes them more likely to form deadly metastases.”

The authors add that these findings could lead to further studies of potential treatments for metastasis, such as therapies that soften tumors to reduce mechanical stress on cancer cells, or that block IAPs. These include SMAC mimetics, which are currently being tested in clinical trials as a possible new therapeutic approach.

Reference: Fanfone D, Wu Z, Mammi J, et al. Confined migration promotes cancer metastasis through anoiki resistance and increased invasion. eLife. 2022;11:e73150. doi: 10.7554/eLife.73150

This article was republished from the following documents. Note: Material may have been edited for length and content. For more information, please contact the quoted source.