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Aug 26, 2014

Cancer Cell Receptors that Guide Metastasis Described

  • Scientists at Duke University say they found a roving detection system on the surface of cells that may point to new ways of treating diseases like cancer, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). The cells, which were studied in nematode worms, are able to break through normal tissue boundaries and burrow into other tissues and organs. This represents a crucial step in many normal developmental processes, ranging from embryonic development and wound-healing to the formation of new blood vessels.

    But sometimes the process goes awry. Such is the case with metastatic cancer, in which cancer cells spread unchecked from where they originated and form tumors in other parts of the body.

    "Cell invasion is one of the most clinically relevant yet least understood aspects of cancer progression," said David Sherwood, Ph.D., an associate professor of biology at Duke and who is leading a team that is investigating the molecular mechanisms that control cell invasion in both normal development and cancer, using C. elegans.

    The Duke researchers published their study, “UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity,” in the Journal of Cell Biology.

    At one point in C. elegans development, a specialized anchor cell breaches the dense, sheet-like membrane that separate the worm's uterus from its vulva, opening up the worm's reproductive tract. Anchor cells can't see, so they need some kind of signal to tell them where to break through. In a 2009 study, Dr. Sherwood and colleagues discovered that a protein called netrin orients the anchor cell so that it invades in the right direction.

    The team’s research paper describes how receptors on the invasive cells essentially rove around the cell membrane hunting for the missing netrin signal that will guide the cell to the correct location.

    “We show that endogenous UNC-6 and ectopically provided UNC-6 orient and stabilize UNC-40 clustering. Furthermore, the UNC-40–binding protein MADD-2 (a TRIM family protein) promotes ligand-independent clustering and robust UNC-40 polarization toward UNC-6,” wrote the investigators. "Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering. We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin."

    The researchers used a video camera attached to a powerful microscope to take time-lapse movies of the slow movement of the C. elegans anchor cell during its invasion. Their time-lapse analyses reveal that when netrin production is blocked, netrin receptors on the surface of the anchor cell periodically cluster, disperse, and reassemble in a different region of the cell membrane. The receptors cluster alongside patches of actin filaments, which help cells change shape and form invasive protrusions, that pop up in each new spot.

    "It's kind of like a missile detection system," noted Dr. Sherwood. Rather than the whole cell having to move around, its receptors move around on the outside of the cell until they get a signal. Once the receptors locate the netrin signal, they stabilize in the region of the cell membrane that is closest to the source of the signal.

    The findings redefine decades-old ideas about how the cell's navigation system works. "Cells don't just passively respond to the netrin signal. They're actively searching for it," added Dr. Sherwood.

    Given that netrin has been found to promote cell invasion in some of the most lethal cancers, the findings could lead to new treatment strategies. Disrupting the cell's netrin detection system, for example, could prevent cancer cells from finding their way to the bloodstream or the lymphatic system and stop them from metastasizing, or becoming invasive and spreading throughout the body.

    Scientists have also known for years that netrin plays a key role in wiring the brain and nervous system by guiding developing nerve cells as they grow and form connections. This means the results could also point to new ways of treating neurological disorders like Parkinson's and ALS and recovering from spinal cord injuries.


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