Stopping a tumor’s ‘cell looting’ may help treat brain cancers

To grow and spread rapidly, some cancer cells steal tiny energy generators from healthy cells.

Glioblastoma is a fast-growing and aggressive brain tumor that often kills patients within a year of diagnosis. Cancer starts in cells called astrocytes, a type of glial cell or “slime cell” that holds neurons in place and helps them function properly. A recent study now reveals that glioblastoma cells fuel their rapid growth by obtaining healthy mitochondria – the powerhouses of the cell – from nearby astrocytes. Blocking this theft of mitochondria may lead to new ways to treat aggressive brain cancers.

That mitochondria jump from healthy cells to cancerous 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 published in nature cancer.

Although mitochondria have previously been shown to move between diseased and healthy cells, it was unclear how this helped cancer spread.

“This is another great example of cancers taking advantage of something that exists in the body to try to spread and grow,” says Eng Lo, a neuroscientist at Massachusetts General Hospital in Boston, who was not involved in the study. ‘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, previously found 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) central nervous system repair mechanism and instead use it to enhance tumor growth,” says Hayakawa.

Mitochondria: powerhouses and signaling hubs

Mitochondria are the primary source of adenosine triphosphate (ATP), a molecule that powers all processes inside every cell. Inside the mitochondria, oxygen molecules react with the metabolic products of glucose to spin a protein motor and make ATP. “We absolutely need mitochondria to survive, because without energy we can’t do anything,” says Minna Roh-Johnson, a biochemist at the University of Utah in Salt Lake City.

“But mitochondria are not only a source of ATP production. They are also the focal point of many cellular pathways to generate many important building blocks of the cell,” says Jiří Neužil, a cell biologist at the Institute of biotechnology from the Czech Academy of Sciences. Science in Prague.

Mitochondria are the main sensors of the local environment. “They sense if there is enough energy – food source – for the cell to grow; there is a danger associated with the local environment; if it is necessary to provide energy for motility or need to kill yourself,” says Danny Welch, a cancer biologist at the University of Kansas Medical Center. Due to 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 laboratory. In 2014, scientists discovered that retinal neurons shed mitochondria, but it was thought that the neurons were merely transferring old and damaged mitochondria to adjacent astrocytes to “recycle” them. Then in 2016, Hayakawa and Lo found that mitochondria could also be swapped in the reverse direction: from healthy astrocytes to damaged neurons. Perhaps this mitochondrial gift is a cellular “help-me” signal that allows astrocytes to defend vulnerable neurons after a stroke, Hayakawa says.

Roh-Johnson research published earlier this year also shows that transferring dysfunctional mitochondria to breast cancer cells stimulates signaling pathways to promote metastasis. However, the mechanism for this transfer has not been worked out.

Lathia’s study, says Roh-Johnson, shows that transferring mitochondria from the healthy cell to the cancerous cell can reprogram the recipients to better adapt to the new environment in the brain.

How to follow the 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 allow cancer to invade healthy cells and grow over long distances.

“We saw that there were a lot of mitochondria in these microtubes, so we came up with the idea of ​​really looking at mitochondrial transfer through the microtubes,” says Hrvoje Miletic, a neuropathologist at the University of Bergen, in Norway, which collaborated with Lathia on the new study.

Hayakawa and Lo’s 2016 study set the stage for Lathia to explore whether cancerous astrocytes could trigger the transfer of mitochondria from healthy cells, just as stroke-damaged neurons acquired them from cells. healthy.

“In the event of a stroke, the neurons die and the astrocytes donate mitochondria to try to resuscitate the neurons,” explains Lathia.

Although it’s physically possible that mitochondrial transfer could also occur in a brain tumor, the implications weren’t obvious, so Lathia and Miletic teamed up to investigate. “Our two independent labs were showing similar results,” says Miletic. “So we thought of getting together and putting our data in one document.”

To track mitochondria transferred through cells, Lathia and Miletic’s team embedded healthy mitochondria, labeled with a protein that glows red under fluorescent light, in mice. Then they injected those same mice with brain tumor cells designed to glow green. “It gave us the best chance to really demonstrate that the transfer was happening,” says Lathia.

The scientists observed the injected green tumor cells steal healthy red mitochondria from their surrounding environment. This provided the strongest evidence to date that the transferred mitochondria came from healthy cells.

What triggers the transfer?

There are many possible ways for mitochondria to move from cell to cell. To figure it out, Lathia and Miletic’s team cultured human glioblastoma cells — tagged with green fluorescent proteins — in a Petri dish with healthy cells containing mitochondria tagged with red fluorescent tags. Under the microscope, they observed that mitochondria moved directly from healthy cells to cancerous cells in the brain via microtubes in direct contact.

Scientists found that between 10 and 20% of human tumor cells in the culture dish received mitochondria from human astrocytes. By stealing healthy mitochondria from astrocytes, 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 that carried only their own mitochondria. Cancer cells with stolen mitochondria were also better at forming tumors.

At first they couldn’t believe it was true, says Miletic. “My PhD student didn’t believe the first results, so he had to repeat the same experiment several times.”

The scientists showed that for mitochondrial transfer to occur, cells had to touch each other and a protein called GAP43 was needed to form the microtubes between astrocytes and glioblastoma cells. “Tumor cells need to be connected to astrocytes via these microtubes,” says Miletic.

Although the new study firmly establishes that this GAP43 protein mediates the formation of microtubes through which mitochondria migrate from healthy astrocytes, it is still unclear why such transfer is triggered in the first place. “(It’s also not clear) how many mitochondria need to enter the tumor cell to make a difference,” says Welch.

However, scientists can now search for drug candidates that can block the transfer of mitochondria from healthy cells to tumor cells. “But for brain tumors, it’s going to be particularly difficult, because you have to get the drug into the brain, in effective concentrations, without affecting normal neural activity,” Lathia says. “It’s going to be a challenge.”

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