Normal in development, abnormal in cancer

By Bruce Lieberman
August 19, 2011
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It’s an amazing and frightening thought: some of the same genetic signaling that shapes the development of an embryo also drives the spread of cancer. But that’s what a new study by Dr. Sara Courtneidge’s lab suggests.

Dr. Courtneidge’s lab primarily studies cancer metastasis—the spread of cancer from a tumor to another part of the body. Cancer cells do this by moving from the tumor through the vasculature and into the extracellular matrix, which provides structural support for tissues and organs. A few years ago, Dr. Courtneidge’s lab showed that cancer cells rely on a protein called Tks5 to form invadopodia, structures on the surface of cells that enable cancer cells to “walk” from one place in the body to another.

Cell migration, of course, is not a process unique to cancer and occurs during other normal and disease states. For example, cells move to the site of a wound during healing, during angiogenesis when new blood vessels form in response to injury, and during an immune response to infection. Cell migration is also crucial during embryonic development. So the Courtneidge lab decided to unravel Tks5’s role in development using the tiny zebrafish as an experimental model.

During initial studies in which expression of the gene that encodes Tks5 was reduced in early zebrafish embryos—resulting in a “morphant embryo”—researchers observed a striking phenotype. Pigmentation defects were among the most obvious changes.

Zebrafish

This led Dr. Danielle Murphy, a postdoctoral researcher in the Courtneidge lab, to wonder where pigment cells originate during embryonic development. So she started reading papers on the subject, eventually learning that these cells originate in the neural crest, a population of embryonic cells that gives rise to a large number of highly migratory cell types—including craniofacial cartilage and bone, parts of the peripheral nervous system, and melanocytes, which are responsible for skin color.

Sure enough, Dr. Murphy found that many of the Tks5-deficient fish had neural crest defects, hence their changes in pigmentation. Through a series of experiments in both cells and zebrafish, she and her colleagues went on to show that Tks5 is vital for early development of the zebrafish embryo. At 48 hours after fertilization, Tks5-deficient morphant embryos displayed smaller heads with small eyes, swelling around the heart, delay in the appearance of pigment cells in the tail, and other abnormalities.

Time-lapse microscopy showed that neural crest cells in Tks5-deficient morphant embryos either did not move at all, moved in the wrong direction, or moved slower than normal embryos. The researchers also observed a reduced number of invadopodia-like extensions (known as podosomes in normal cells), those cellular protrusions akin to feet that help the cell move during migration. The podosomes appeared to be dependent on Tks5.

Discovering this role for Tks5 in neural crest biology – which was already known as a key player in cancer metastasis – “was pretty exciting for us,” Dr. Murphy says. “This is really the first time anyone has seen that neural crest cells can actually form podosomes, or that Tks5, a podosome-associated protein, is required for neural crest cell migration during development.”

Dr. Murphy, Dr. Courtneidge, and their colleagues published these results July 25 in the journal PLoS ONE.

On the surface, cancer cells and neural crest cells seem to come from two different worlds. Neural crest cells are highly programmed to migrate to specific locations in the embryo, where the cells of an adult eventually are derived. Cancer cells, by contrast, are constantly adapting new ways to work around the body’s defenses.

Yet this Tks5 story shows that the two processes—development and cancer—have more in common than one might think, and that studying the biology of one may illuminate the biology of the other.

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Original Paper:

Murphy DA, Diaz B, Bromann PA, Tsai JH, Kawakami Y, Maurer J, Stewart RA, Izpisúa-Belmonte JC, & Courtneidge SA (2011). A Src-Tks5 Pathway Is Required for Neural Crest Cell Migration during Embryonic Development. PloS one, 6 (7) PMID: 21799874

ResearchBlogging.org

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