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Researcher Joan Massagué makes a breakthrough in understanding the cause of cancer metastasis

Cells leave the primary tumor and hide from the immune system for months or years by infiltrating other organs disguised as stem cells

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06.04.2016

Medicine does not yet have the tools to prevent metastasis, which is the cause of most of the deaths caused by cancer. Metastasis can occur many years after the tumor has been detected, treated and eradicated. While primary tumors do not always affect the body's vital organs, metastasis usually does. At the moment the only recourse is early detection, but thanks to a research group led by Joan Massagué, new treatments could be designed to prevent metastasis, even when dealing with latent metastasis.

Joan Massagué, researcher and director of the Memorial Sloan Kettering Cancer Center, has discovered that some of the tumor cells that are released from the primary tumor and enter the bloodstream manage to get past the immune system, which would normally destroy them, and they settle in other organs, hidden for months or years. They do this by becoming stem cells and reducing their activity to a minimum, going undetected by the natural killer cells in the immune system, which destroy cancerous cells.

When the cells manage to settle in an organ, this is known as latent metastasis. It is not always the case, but sometimes the immune system's defenses do not manage to keep the cancerous cells at bay and metastasis occurs.

Massagué's work explains that while “pretending” to be stem cells, the cancerous cells enter a state of inactivity and, like other cells in the same state, they do not proliferate. But at some point they go into action and multiply. The new cancerous cells are detected by the natural killer cells, which then destroy them. But they are unable to destroy the initial latent cells, which become inactive once more.

The way that these cells "disguise themselves" as stem cells is by inhibiting the WNT protein group, which triggers the cells' inactive state and means they stop producing the molecules that the natural killer cells “smell” to detect and destroy carcinogens.

 

Breast and lung cancer

Joan Massagué's research group focused their research, which was published in the journal Cell, on two types of cancer: breast cancer and lung cancer. The experiments were carried out on developing cell cultures for patients and mice with these types of cancer. These experiments allowed researchers to observe the metastatic cells escape from the primary tumor and hide elsewhere.

In the case of lung cancer, these cells managed to hide in organs such as the kidneys and brain. The breast cancer cells hid in the lungs. The initial latent cells escaped from the natural killer cells in the immune system by activating two proteins that regulate multiple genes and change cell behavior (known by molecular biologists as transcription factors).

The lung cancer cells activated the SOX2 protein, while the breast cancer cells activated the SOX9 protein. It is thanks to this mechanism that cancerous cells become stem cells.

This finding opens the door for new strategies to prevent metastasis. There is the possibility of developing drugs that would force cells to come out from hiding and show the signs that make them visible and proliferate, so that they could be destroyed by the immune system.

However, this runs the risk of causing metastasis that might otherwise never have occurred. Using this research as a starting point, the aim is to find a more subtle immunotherapy to fight against latent metastasis.

 

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Joan Massagué

Joan Massagué directed the Cell Biology and Genetics program at the Memorial Sloan Kettering Hospital in New York for many years, before specializing in metastasis. He is one of the founders of the IRB Barcelona (see photo).

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