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BySanjay Mishra
Published June 23, 2023
• 8 min read
To grow and spread rapidly, some cancer cells steal tiny power generators from healthy cells.
Glioblastoma is a fast-growing and aggressive brain tumor that often kills patients within a year of diagnosis. The cancer starts in the cells called astrocytes, a type of glial or “glue cell” that hold the neurons in place and help them function properly. A recent study now reveals that glioblastoma cells fuel their speedy growth by getting healthy mitochondria—the powerhouses of the cell—from neighboring astrocytes. Blocking this theft of mitochondria may lead to new ways to treat aggressive brain cancers.
That mitochondria would move from healthy cells to cancer cells is “a bit of a crazy idea,” says Justin Lathia, a cancer biologist at the Cleveland Clinic Lerner Research Institute who led the study that was published in Nature Cancer.
Although mitochondria have been previously shown to move between diseased and healthy cells, it wasn’t clear how this helped the cancer to spread.
“This is another great example of cancers taking advantage of something that exists within the body to try and spread and grow,” says Eng Lo, a neuroscientist at Massachusetts General Hospital in Boston, who was not involved in the study. “Cancers can be so insidious that they can really hijack many processes to enable their own survival and spread.”
Lo and Kazuhide Hayakawa, a fellow neuroscientist at Massachusetts General Hospital, had previously discovered that mitochondria are transferred from astrocytes to damaged neurons after a stroke.
“This [new] study is exciting, because it shows how cancers hijack an [important] mechanism of central nervous system repair and use it to enhance tumor growth instead,” says Hayakawa.
Mitochondria: powerhouses and the signaling hubs
Mitochondria are the main source of adenosine triphosphate (ATP), a molecule that powers all the processes inside every cell. Inside mitochondria, oxygen molecules react with metabolic products of glucose to spin a protein motor and manufacture ATP. “We absolutely need mitochondria to survive, because without energy, we can’t do anything,” says Minna Roh-Johnson, a biochemist at University of Utah in Salt Lake City.
“But mitochondria are not just a source of ATP production. They are also the converging point of lots of cellular pathways for generating many important building blocks of the cell,” says Jiří Neužil, a cell biologist at Institute of Biotechnology of the Czech Academy of Sciences in Prague.
Mitochondria are the key sensors for the local environment. “They sense if there is enough energy—food source—for the cell to grow; there is danger associated with the local environment; whether there is need to either provide energy for motility; or need to commit suicide,” says Danny Welch, a cancer biologist at The University of Kansas Medical Center. Because of their critical role, the transfer of mitochondria is considered one of the hallmarks of cancer.
Scientists first discovered in 2006 that mitochondria are transferred between cells grown together in a dish in the lab. In 2014, scientists found that neurons from retina shed mitochondria, but it was thought that neurons were just transferring old and damaged mitochondria to adjacent astrocytes for “recycling.” Then in 2016, Hayakawa and Lo discovered that mitochondria could also be exchanged in the opposite direction: from healthy astrocytes to damaged neurons. Maybe this mitochondrial donation is a cellular “help-me” signal that allows astrocytes to defend vulnerable neurons after a stroke, Hayakawa says.
Roh-Johnson’s research published earlier this year also shows that transfer of dysfunctional mitochondria to breast cancer cells stimulates signaling pathways to promote metastasis. However, the mechanism of this transfer was not worked out.
Lathia’s study, says Roh-Johnson, shows that the transfer of mitochondria from the healthy cell to the cancer cell can reprogram the recipients to fit better to the new environment in the brain.
How to track movement of mitochondria?
In 2015, scientists discovered that in brain tumors such as glioblastomas, microscopic tubes form networks between cancer cells. These microtubes connect cancer cells and provide routes for cancer to invade healthy cells and proliferate over long distances.
“We saw that there were a lot of mitochondria in these microtubes, so we had the idea to really look into mitochondrial transfer through microtubes,” says Hrvoje Miletic, a neuropathologist at the University of Bergen, Norway, who collaborated with Lathia on the new study.
Hayakawa and Lo’s 2016 study set the stage for Lathia to explore whether the cancerous astrocytes could instigate the transfer of mitochondria from healthy cells, just as stroke-damaged neurons acquired them from healthy cells.
“In stroke, neurons are dying and the astrocytes donate mitochondria to try to resuscitate neurons,” says Lathia. “We had just gone into this first being surprised that the transfer could occur.”
While it was physically possible for the mitochondrial transfer to also occur in a brain tumor, it was not obvious what the implications would be, so Lathia and Miletic teamed up to investigate. “Our two independent labs were showing similar results,” says Miletic. “So we thought to come together and put our data into one paper.”
To track the mitochondria being transferred across the cells, Lathia and Miletic’s team embedded the healthy mitochondria—labeled with a protein that glows red in fluorescent light—in mice. Then they injected those same mice with brain tumor cells that were engineered to glow green. “That gave us the best chance to really demonstrate the transfer was occurring,” says Lathia.
The scientists watched the injected green tumor cells steal the healthy, red mitochondria from their surrounding environment. This provided the strongest evidence to date that the transferred mitochondria originated from healthy cells.
What triggers the transfer?
There are many possible ways mitochondria could move from cell to cell. To figure it out, Lathia and Miletic’s team grew human glioblastoma cells—labeled with green fluorescent proteins—in petri dish with healthy cells containing mitochondria labeled with red fluorescent tags. Under a microscope, they observed the mitochondria move directly from healthy cells to brain cancer cells via microtubes on direct contact.
Scientists found that between 10 to 20 percent of the human tumor cells in the culture dish received mitochondria from the human astrocytes. By stealing healthy mitochondria from the astrocytes, the tumor cells could consume more oxygen and grow faster. The study shows that glioblastoma cells implanted in mice that carried many mitochondria stolen from astrocytes proliferated more aggressively than those carrying only their own mitochondria. The cancer cells with stolen mitochondria were also better at forming tumors.
At first, they couldn’t believe that this was true, says Miletic. “My PhD student couldn’t believe the first results, so he had to repeat the same experiment several times.”
The scientists showed that for mitochondrial transfer to happen, the cells had to touch each other and a protein called GAP43 was needed to form the microtubes between astrocytes and glioblastoma cells. “The tumor cells need to be connected to the astrocytes through these microtubes,” says Miletic.
Although the new study firmly establishes that this GAP43 protein mediates formation of microtube through which the mitochondria migrate from the healthy astrocytes, it is still not known why such a transfer is triggered in the first place. “[It is also not clear] how many mitochondria have to get into the tumor cell to make a difference” says Welch.
However, scientists can now screen for candidate drugs that can block transfer of mitochondria from healthy to tumor cells. “But for brain tumors, it is going to be especially difficult, because you have to get the drug into the brain, at effective concentrations, without impacting normal neural activity,” says Lathia. “That’s going to be a challenge.”
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