This metastasis animation shows the primary tumor. [Barts Cancer Institute, QMUL]
This metastasis animation shows the primary tumor. [Barts Cancer Institute, QMUL]

Cancer cells appear to depend on an unusual survival mechanism to spread around the body, according to a research study led by Queen Mary University of London (QMUL). The scientists believe the discovery could help with future development of novel treatments to prevent metastasis and secondary tumors.

A key question has been how cancer cells are able to survive once they metastasize. Cells are relatively protected when they are attached to other cancer cells and their surroundings, but they become more vulnerable when they detach and float and normally undergo cell death.

Lead researcher Stéphanie Kermorgant, Ph.D., from QMUL's Barts Cancer Institute, noted that “Metastasis is currently incurable and remains one of the key targets of cancer research. Our research advances the knowledge of how two key molecules communicate and work together to help cancer cells survive during metastasis. We're hoping that this might lead to the discovery of new drugs to block the spread of cancer within the body.”

The study (“Beta 1-Integrin–c-Met Cooperation Reveals an Inside-In Survival Signalling on Autophagy-Related Endomembranes”), published in Nature Communications, examined the changes that occur in cancer cells as they break away from tumors in cell cultures, zebrafish, and mice. The researchers revealed a previously unknown survival mechanism in cancer cells and found that integrins could be key. These proteins on the cell surface attach to and interact with the cell's surroundings. “Outside-in” and “inside-out” signaling by integrins is known to help the cancer cells attach themselves to their surroundings. But the study suggests that when the cancer cells are floating, as they do during metastasis, the integrins switch from their adhesion role to take on an entirely new form of communication that has never been seen before, I.e., inside-in signaling, in which integrins signal within the cell.

The researchers discovered that an integrin called beta-1 (β1) pairs up with another protein called c-Met and they move inside the cell together. The two proteins then travel to an unexpected location within the cell that is normally used to degrade and recycle cell material. Instead the location is used for a new role of cell communication, and the two proteins send a message to the rest of the cell to resist death while floating during metastasis.

Using both breast and lung cells, the team found that metastases were less likely to form when β1 and c-Met were blocked from entering the cell together or were prevented from moving to the special location within the cell.

Integrins are already major targets for cancer treatment, with drugs either being tested or in use in the clinic. Most integrin inhibitor drugs target their adhesive function and block it on the surface of the cancer cell. The researchers say that the limited success of these drugs could be partly explained by this newly discovered role of integrins within the cancer cell.

A new strategy could be to prevent the integrin from going inside the cell in the first place. The researchers hope that these insights could lead to the design of better therapies against metastasis and more effective treatment combinations that could prevent and slow both tumor growth and spread.








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