• Getting fuel to an invading cell's front

    From ScienceDaily@1:317/3 to All on Tuesday, March 22, 2022 22:30:48
    Getting fuel to an invading cell's front line
    From a tiny worm, new clues to how metastatic cancer cells power their
    deadly spread

    Date:
    March 22, 2022
    Source:
    Duke University
    Summary:
    Invading armies need a steady supply of fuel and armaments. That's
    just as true when the invaders are cells, such as when tumor cells
    break away and spread to other parts of the body in a process
    called metastasis - - the most deadly part of cancer. Now, a
    study in C. elegans worms provides new insight into how invading
    cells deploy fuel to the front lines of invasion to power their
    break-through machinery.



    FULL STORY ========================================================================== Invading armies need a steady supply of fuel and armaments. That's just
    as true when the invaders are cells, such as when tumor cells break away
    from their neighbors and spread to other parts of the body in a process
    called metastasis -- the most deadly part of cancer.


    ==========================================================================
    Now, a Duke University-led study in the tiny worm C. elegans provides
    new insight into how invading cells amass and deploy fuel to the front
    lines of invasion to power their cellular break-through machinery.

    In a study in the journal Developmental Cell, Duke biology professor David Sherwood and colleagues have identified two glucose transporters that,
    when deactivated, disrupt the energy supply to 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.

    "This is a big deal because it gives us a new aspect of invasive cells
    to target therapeutically," Sherwood said.

    Metastatic cancer is notoriously difficult to treat. Most cancer drugs
    work by destroying tumor cells or slowing their growth. But very few of
    the more than 200 anti-cancer drugs that have been approved for clinical
    use actually prevent cancer from breaking off from the original tumor
    and spreading to other organs -- the culprit behind the vast majority
    of cancer-related deaths.



    ==========================================================================
    "We have no therapies to target this step as we don't have a good
    understanding of how cells breach tissue barriers," said Sherwood, the
    senior author of the paper. "It's ironic, because it's the most lethal
    aspect of cancer, but the one that we understand the least." Part of
    the reason is the process has been hard to study. Cancer's spread is unpredictable, and most cancer cells metastasize deep within the body,
    beyond the reach of light microscopes.

    "It's hard to spot an invasive cell in the act," Sherwood said.

    So Sherwood's lab studies a similar process in millimeter-long transparent worms called C. elegans. Before a developing worm can finish building
    its reproductive tract, a specialized cell called the anchor cell must
    break through the dense, sheet-like mesh that separates the worm's uterus
    from its vulva to clear a path for mating and laying eggs.

    Both worm cells and human cancer cells use the same invasive machinery:
    a barrage of piston-like projections that sprout from the cell surface
    and pummel their way through tissue barriers to clear a path for cells
    to pass through, like punching out an escape tunnel.



    ==========================================================================
    The question is, "what's fueling these machines?" said first author
    Aastha Garde, a doctoral student in cell biology at Duke. "And can we
    target that instead of the machines themselves, to deprive them of their
    source of energy so the machines stop working?" The researchers used
    a camera attached to a powerful microscope to peer inside tiny worm
    cells hundreds of times smaller than a grain of sand and watch their "break-ins" in action.

    Garde showed off a time-lapse of an invading cell as it pushed and wedged
    its way into neighboring tissues. The cell had been engineered 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 break through, 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 energy
    factories of the cell -- that are guided to the cell's front lines of
    invasion by a molecular cue called netrin, the researchers show.

    The researchers also screened 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 cells were still able to break through.

    They identified two genes that encode gate-like proteins called FGT-1
    and FGT- 2. These build up along the cell's borders just before invasion
    and let more glucose into the cell, where it is broken down to make ATP.

    When the researchers deactivated these genes, glucose and ATP levels
    dropped, and the worm cells stalled their spread. Through the microscope,
    they could see cells making a feeble effort to put out new piston-like projections, to push through, but most were delayed, and a third of the
    cells stopped advancing altogether.

    "Without glucose, basically the entire machinery that the anchor cell
    uses to bust through the basement membrane is impaired," Garde said.

    There's a lot scientists still don't know about what makes cancer cells metastasize. But the researchers hope their work on worms will help them
    "find out the Achilles heel of cell invasion," Sherwood said.

    "This is an aspect of how cells breach that's been largely overlooked," Sherwood said. "If we can halt this burst of ATP, we can limit or stop
    cell invasion." This research was supported by the National Institutes
    of Health (R35GM118049- 06, R01AG045183, R01AT009050, DP1DK113644, P40 OD010440), March of Dimes Foundation, Welch Foundation, and the Howard
    Hughes Medical Institute.


    ========================================================================== Story Source: Materials provided by Duke_University. Original written
    by Robin Smith. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Aastha Garde, Isabel W. Kenny, Laura C. Kelley, Qiuyi Chi, Ayse Sena
    Mutlu, Meng C. Wang, David R. Sherwood. Localized glucose import,
    glycolytic processing, and mitochondria generate a focused ATP
    burst to power basement-membrane invasion. Developmental Cell,
    2022; DOI: 10.1016/ j.devcel.2022.02.019 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220322154222.htm

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