Metastatic cancer is difficult to prevent. Could RIPK1 help?
The process through which cancer cells break free of their primary sites and migrate into nearby and distant tissue is known as metastasis.
It is the "main reason" that cancer is such a serious disease.
Once metastasis is under way, the disease is much harder to control and few cancers can be cured once they become metastatic.
Detaching from the extracellular matrix
In a report on the results that was published recently in the journal Nature Cell Biology, researchers from the University of Notre Dame in Indiana explain how cancer cells must first detach themselves from the extracellular matrix — or the "protein scaffold" that normally holds cells in place — before they can start to migrate.
To successfully break free, cancer cells must defeat various mechanisms that normally trigger cell death when cells detach from the extracellular matrix. As tumors develop, their cells can become resistant to these mechanisms.
Previous research suggested that one such mechanism may work by increasing oxidative stress on the cell, but the details have remained "poorly defined," note the authors.
The new study investigated a cell enzyme called receptor-interacting protein kinase 1 (RIPK1), which was already known to play a role in a type of cell death called necrosis.
A surprising new role for RIPK1 in cell death
While they were investigating RIPK1, the scientists were surprised to find that the enzyme seemed to have an effect on mitochondria, suggesting a role in a completely different type of cell death.
"We really thought," explains senior study author Zachary Schafer, an associate professor of cancer biology, "this was going to be a story about necrosis, but we weren't able to see evidence of it, and knew there had to be something we're missing."
He and his colleagues revealed that activation of RIPK1 as the cell detaches from the extracellular matrix triggers a process called mitophagy that degrades mitochondria, which are the tiny cellular compartments — sometimes referred to as "powerhouses" — that supply most of the cell's energy.
The mitophagy triggers further reactions in the detached cell that increase levels of reactive oxygen species, or the compounds that cause the oxidative stress that leads to cell death.
"Looking at mitochondrial numbers fundamentally changed our thinking, and got us focused on a different way that RIPK1 may cause cells to die."
Prof. Zachary Schafer
Further tests revealed that blocking the relevant RIPK1 pathway promoted tumor formation in a live model.
The study authors conclude that their findings suggest that targeting the "RIPK1-mediated induction of mitophagy" might be an effective way to stop tumors from spreading by eliminating cancer cells that detach from the extracellular matrix.