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FEATURES: Cells on the Move
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Jason Cyster studies the molecular cues that guide immune cells as they mature within lymph nodes and then move out into the body.
The take-home message is that coordinating external signals with cytoskeletal rearrangement is astonishingly complex, which could be good news: the more complex the process, the more opportunities for intervention. Take cancer cells, for example. Bear points out that in terms of motility, metastasizing cancer cells, though frighteningly effective, may just be generalists. “Metastatic cells are like the winners of the decathlon,” he says. “They have to win 10 different events but only passably well.” Tripping over a hurdle may be sufficient to put them out of the game.
Actin and its brancher, the Arp 2/3 complex, are the nuts and bolts of the cytoskeleton and therefore may not be good starting points for designing drugs to perturb motility in a targeted way. Better candidates may be found in specialized actin bundlers or cross-linkers, which mold the scaffolding underlying specialized “feet” and other protrusions.
Among the bundlers is a group of proteins called coronins. In successive Cell articles, published in 2007 and 2008, Bear reported that an actin-binding protein called coronin 1B controlled the extent of actin branching by putting the brakes on the Arp 2/3 complex. Without coronin 1B, the cytoskeletal network was elaborate but rigid, causing fibroblasts to move more slowly—a big liability for a wound healer.
A different coronin, subtype 1A, appears critical for avoiding catastrophic immobilization of immune cells. Collaborating with Bear, HHMI investigator Jason Cyster reported in a 2008 Nature Immunology paper that in mice with a mutation in the gene encoding coronin 1A, T lymphocytes could not exit their birthplace, the thymus, to activate an immune response in peripheral tissues.
T lymphocytes with a mutation in the gene encoding coronin 1A (ptcd T cells) are more rigid and move more slowly than wild type cells. Reprinted by permission from Macmillan Publishers Ltd: Nature Immunology (9: 1307-13015), copyright 2008.
“These mutant mice have no peripheral T cells and were highly immune compromised,” says Cyster, of the University of California, San Francisco (UCSF). The researchers also reported that a patient with severe combined immunodeficiency, or SCID, had coronin 1A mutations, suggesting that perturbing actin branching in a way that paralyzes cells is not insignificant but rather promotes a deadly disease.
Metastasizing cancer cells show protrusions reminiscent of lamellipodia but they are likely specialized for specific cellular environments. Some cancer cells express high levels of yet another coronin, coronin 1C, suggesting that changes in actin branching may enhance tumor cell invasion. Bear’s lab is examining cultured cells and animal models to determine whether upregulation of coronin 1C stimulates actin cycling in a way that enhances motility in human melanoma cells.
A newly generated T cell (red) in the act of migrating out of the thymus into a blood vessel (green). The nuclei of several surrounding cells are shown in blue. This process is essential for establishing a functional immune system. Image: Marcus Zachariah and Jason Cyster
For most of his career, cancer researcher Massagué has investigated signals that fire up the cytoskeletal engine; he is also evaluating the effect of actin-interacting proteins on metastasis. In 2005, his lab group identified 18 “signature” genes associated with lung metastasis of human breast cancer. Most of them encoded factors that cells use for communication, like cytokines and their receptors. But one, called fascin, encoded a protein that bundles actin filaments into rods supporting spiky protrusions called invadopodia (picture lean lamellipodia armed with pickaxes). Blood and muscle cells occasionally use invadopodia to grasp a surface, but they are most common in tumor cells.
“Cells use fascin protrusions to pry through layers of cells—for example, those lining lung capillaries,” says Massagué. “It makes complete sense that breast cancer cells would find a way through the bloodstream into the lungs by augmenting invadopodia power.”
Japanese scientists seeking tumor inhibitors based on natural products have identified an anti-fascin molecule called migrastatin from Streptomyces platensis bacteria. Massagué and chemist Samuel Danishefsky, of Columbia University and Memorial Sloan-Kettering Cancer Center, have teamed up to create and test potent migrastatin analogs to slow movement of metastatic cells; in work published September 13, 2011, in the Proceedings of the National Academy of Sciences, Danishefsky reported that some of those analogs effectively block metastasis to several sites, including liver, heart, kidneys, and spleen, in a mouse model of human lung cancer.