Cells' trash disposal system shapes as a "toggle" for cancer treatment
The techniques our cells use to dispose of waste products offers some exciting avenues for us to potentially intervene in their behavior, whether it's clogging up these garbage disposal systems to bring cancer undone or repairing their defects to tackle Alzheimer's. Research from MIT has shown how this activity is ramped up during cell division, with the newly discovered mechanism potentially offering scientists a "toggle" for treating these kinds of diseases.
The breakthrough centers on cellular cleaning organelles called lysosomes, and came about as the MIT researchers developed a new way to measure the dry mass of cells. This technique was years in the making and involves comparing measurements of the cell in normal water and in heavy water dosed with deuterium, from which they can then calculate its dry mass. The technique is billed as an advance on a couple of fronts. Heavy water is toxic to cells so previous approaches have only enabled one measurement per cell, whereas this system allows for repeated measurements. It also offers insights into the cell's density and makeup.
"Our idea was that if we minimize the cells’ exposure to the heavy water, we could engineer the system so that we could repeat this measurement over extended time periods without hurting the cell," said lead author of the study Teemu Miettinen. "That enabled us for the first time to track not just the dry mass of a cell, which is what others do using microscopic methods, but also the density of the dry mass, which informs us of the cell’s biomolecular composition."
This new tool was deployed as a way of studying a type of cell division called mitosis, with the scientists seeking to learn what happens to cell mass and composition throughout. Experiments were carried out on cancer cells, which divide more frequently than regular healthy cells, and the scientists found that the dry mass actually decreased as the cells entered mitosis, with that mass regained again once the cell division was complete.
Further investigations revealed that as the cells were going into mitosis, they were ramping up activity of the lysosomes. These cell organelles are responsible for breaking down and disposing of cellular waste products through a process called exocytosis. The lysosomes were doing so with such fervor that the cells were losing about four percent of their mass during division.
“Our hypothesis is that cells might be throwing out things that are building up, toxic components or just things that don’t function properly that you don’t want to have there," said Miettinen. "It could allow the newborn cells to be born with more functional contents."
The discovery of this mechanism could have implications for the way we treat disease. Cancer cells divide frequently, and are known to expel some chemotherapy drugs through exocytosis, which helps them become resistant to treatments. The thinking is that if exocytosis can be prevented it could make the cancer cells more vulnerable to such therapies.
On the other side of the coin, nerve cells in the brain don't divide at all, which means they wouldn't experience this phase pf heightened lysosome exocytosis. This in theory leaves the door ajar for the accumulation of toxic amyloid and tau proteins that are associated with the onset of Alzheimer's.
We have seen lysosome activity implicated in Alzheimer's research before. One 2019 study demonstrated how these toxic proteins can flip their molecular structure to present a mirror image of themselves to the lysosomes, essentially making them indigestible and unable to be cleared away. Other research has put forward the idea that the build-up of dysfunctional lysosomes in the brain actually accelerates the accumulation of the proteins, and removing the failed lysosomes could be a form of treatment.
This new understanding of lysosome activity and its role in cell division raises yet more interesting possibilities in the treatment of not just Alzheimer's, but other diseases as well. Finding a way to manipulate this mechanism could effectively provide us with a switch to shape the way cells clear out toxic products.
“There are diseases where we might want upregulate exocytosis, for example in neurodegenerative diseases, but then there are diseases like cancer where maybe we want to dial it down,” Miettinen says. “In the future, if we could better understand the molecular mechanism behind this, and find a way to trigger it outside of mitosis or prevent it during mitosis, we could really have a new toggle to use when treating disease.”
The research was published in the journal eLife.