Invading armies need a steady supply of fuel and armaments. This is just as true when the invaders are cells, as when tumor cells separate from their neighbors and spread to other parts of the body in a process called metastasis – the deadliest part of cancer.
Now, a Duke University-led study into the little ver C.elegans provides new insight into how invading cells accumulate and deploy fuel to the front lines of invasion to power their cellular breakthrough machinery.
In a study from the journal Development cellDuke biology professor David Sherwood and his colleagues have identified two glucose transporters that, when turned off, disrupt the energy supply of invading worm cells and even stop some of them in their tracks.
The findings could eventually lead to new ways to cut the supply lines that allow cancer cells to metastasize in humans.
“It’s a big deal because it gives us a new look at invasive cells to target therapeutically,” Sherwood said.
Metastatic cancer is notoriously difficult to treat. Most cancer drugs work by killing tumor cells or slowing their growth. But very few of the more than 200 cancer drugs that have been approved for clinical use actually prevent cancer from breaking away from the original tumor and spreading to other organs – the culprit of the vast majority of cancer-related deaths. Cancer.
“We don’t have therapies to target this step because we don’t fully understand how cells cross tissue barriers,” said Sherwood, the paper’s lead author. “It’s ironic, because it’s the deadliest aspect of cancer, but the one we understand the least.”
Part of the reason is that the process has been difficult to study. The spread of cancer is unpredictable and most cancer cells metastasize deep in the body, beyond the reach of light microscopes.
“It’s hard to spot an invasive cell in the act,” Sherwood said.
Sherwood’s lab is therefore studying a similar process in millimeter-long transparent worms called C.elegans. Before a developing worm can finish building its reproductive system, a specialized cell called an anchor cell must break through the dense, leaf-like mesh that separates the worm’s uterus from its vulva to clear a path for the mating and egg laying.
Worm cells and human cancer cells use the same invasive machinery: a barrage of piston-like projections that sprout from the cell’s surface and push their way through tissue barriers to clear a path for cells to pass through. , like drilling an escape tunnel.
The question is, “what powers these machines?” said first author Aastha Garde, a doctoral candidate in cell biology at Duke. “And can we target that instead of the machines themselves, to deprive them of their power source so that the machines stop working?”
The researchers used a camera attached to a powerful microscope to look inside tiny worm cells hundreds of times smaller than a grain of sand and watch their “break-ins” in action.
Garde showed a time lapse of an invading cell as it pushed and squeezed into nearby tissue. The cell had been designed with a sensor that lights up whenever an energy-carrying molecule called ATP reaches a certain level, like a cellular fuel gauge. Just as the cell was about to breach, a burst of light appeared behind the cell’s front lines, revealing an outpouring of ATP at the time of the breach.
This ATP is produced by organelles called mitochondria – the cell’s energy factories – which are guided to the cell’s first lines of invasion by a molecular signal called netrin, the researchers show.
The researchers also sifted through some 8,300 of the worm’s roughly 20,000 genes, silencing them one by one using a technique called RNA interference to see if the worm’s cells were still able to break through.
They identified two genes that code for gate-like proteins called FGT-1 and FGT-2. These accumulate along the borders of the cell just before invasion and let more glucose into the cell, where it is broken down to make ATP.
When the researchers turned off these genes, glucose and ATP levels dropped, and the worm cells blocked their spread. Under the microscope, they could see cells making a weak effort to emit new piston-like projections, to push through, but most were delayed and a third of the cells stopped moving altogether.
“Without glucose, virtually all of the machinery that the anchor cell uses to cross the basement membrane is impaired,” Garde said.
There are many scientists who still don’t know what causes cancer cells to metastasize. But the researchers hope their work on the worms will help them “uncover the Achilles’ heel of cell invasion,” Sherwood said.
“This is an aspect of cell disruption that has been largely overlooked,” Sherwood said. “If we can stop this explosion of ATP, we can limit or stop cell invasion.”
Reference: Guard A, Kenny IW, Kelley LC, et al. Localized glucose import, glycolytic processing, and mitochondria generate a targeted ATP surge to fuel basement membrane invasion. Development cell. 2022.doi:10.1016/j.devcel.2022.02.019
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