Mark McNiven, Ph.D., who directs the Cancer Cell Biology program at Mayo Clinic Cancer Center, is unusually fascinated by visual delights. On a bike ride, he finds it impossible to pass by a pretty but lifeless butterfly, which soon joins many of its cousins and one hummingbird in an artfully arranged road kill display on his wall. It is one of captivating feasts for the eyes that decorate his office and lab. It is not surprising that his optical fascination extends to the enchanting world revealed by the computer-run light and electron microscope; in his case, a world populated by lamellipods, vesicles, filaments and microtubules.

Early on in his science career, Dr. McNiven worked at the Marine Biological Laboratory on Cape Cod, Mass., where he studied how neurons transport specific messages. He kept working on this process through his postgraduate studies at the University of Maryland, then as a postdoctoral fellow at Johns Hopkins Medical School before coming to Mayo Clinic.

"At that time, back in the late 70s and early 80s, the mechanisms of cell movement were almost completely undefined," he says. "Today we know much more about how cells grow and move and that's helping us to understand disease processes."

Green Light for Neuron Movement; Red Light for Cancer Cells

The proteins, signaling cascades and other components used by a neuron to move and connect with other neurons are very similar to the mechanisms used by a tumor cell to invade. Because of this the McNiven lab studies movement in normal embryo neurons in culture and compares it with migration of human pancreatic tumor cells.

Dr. McNiven has two research grants from the National Institutes of Health to study cytoskeletal dynamics, one in pancreatic cancer metastasis and the other in its regulation of vesicular transport in liver cells. The cytoskeleton, the cell's skeleton, is composed of protein filaments and microtubules within the cytoplasm. Its function is to maintain cell shape, move the cell along, and move many small structures within it. It also plays an important role in cell division. A vesicle is a tiny sack that encloses substances within its membrane and transports them.

The Little Engines That Could

The lamellipod is made up of protein molecules or enzymes such as myosins and dynamin, which scientists call mechano-enzymes. The McNiven lab is trying to unearth how these enzymes work in synchrony to support movement.

"There are whole sets of mechano-enzymes in cells--hundreds of them--that store energy like ATP (adenosine-5'-triphosphate) and convert it to move vesicles through the cytoplasm or cells along their environment," explains Dr. McNiven. "They're little biomotors, each with unique functions. Each motor moves along a filament not unlike a train engine on a track. Myosins in muscles are the best known of them. For example, when you flex your muscle, millions of myosin molecules ratchet along a filament to help move it."

Of particular interest to the McNiven lab is a family of mechano-enzymes called dynamin, that bind to cytoskeletal filaments to pinch cell membranes, and the roles it plays in the interaction of the cell membrane and the cytoskeleton. The team has achieved recognition in their field for discovering several types of dynamins.

Endocytosis

Dynamin plays an important role in endocytosis -- a process used by the cell to import structures that are too big to fit through the pores of the cell membrane. In endocytosis, a portion of the cell membrane wraps around the structure and folds inward to form a sac, called a vesicle, which is then pinched off and released into the cytoplasm.

One pathway for endocytosis, called receptor-mediated endocytosis, is initiated by a protein, called clathrin, to form a crystalline coat on the inner surface of the cell membrane in preparation for vesicle formation. Dynamin influences the rate that early forms of these vesicles are released from the plasma membrane during endocytosis.

Endocytosis is essential for all cells as it brings in nutrition such as iron, and protein into cells, and helps to clear the blood of unwanted substances such as fat and toxins.

"This process also brings things into cells that we don't want, such as parasites, bacteria and viruses that hijack the cell," says Dr. McNiven. "Trying to understand how to prevent this is a major focus of our lab."

In this area, Dr. McNiven collaborates with immunology researcher Daniel Billadeau, Ph.D., who studies the role that dynamin plays in white blood cells to help their major function, killing other cells that are invading the body. Their papers include a study of how dynamin-2 regulates T cell activation (Nature Immunology, 2005. 6(3):261-70).

The McNiven team was the first to show how a component of the actin cytoskeleton, called cortactin, binds with dynamin (Molecular and Cellular Biology, 2003. 23 (6): 2162-2170). The proteins line up in the leading lamellipodia of migrating tumor cells and appear to play an essential role in cytoskeletal reconstruction as the tumor cell prepares to migrate and metastasize. The results of the lab's cultured cell experiments suggested that cortactin provides a direct link between the cytoskeleton and dynamin to allow vesicle formation during receptor-mediated endocytosis.

The same machinery that helps cells extend a lamellipod and move along is also used by invading parasites to attach to cells. Dr. McNiven collaborates with digestive disease researcher Nicholas LaRusso, M.D. Dr. LaRusso studies a parasite called cryptosporidia, which constitutes a minor public health problem when it gets into a city's water supply or pool water in water parks because it causes watery diarrhea in healthy individuals. It is a substantial health problem in third world countries.

Dr. LaRusso, however, is much more concerned with its effect on people with AIDS in whom it can induce severe liver disease. In 1993, a waterborne outbreak led to 400,000 cases of cryptosporidiosis in Milwaukee, Wisc., and resulted in at least 100 deaths in patients with AIDS. Collaboration between the two research teams has shown that dynamin and other associated proteins mediate the invasion of the parasite to healthy liver cells and can prevent the infection by inhibiting dynamin function.

Cellular Waves

Belying the static representation in your high school biology book, cells are hives of activity. Scientists have even observed waves, which they call circular dorsal ruffles, rippling on the surface of the cell membrane for 10 to 20 minutes and wondered why they were there. In a series of experiments, the McNiven lab has made significant contributions to understanding the function of these waves.

The McNiven team was the first to show the correlation between formation of lamellipodia and wave-induced reorganization within a cell (Nature Reviews Molecular Cell Biology, 2004. 5:647-657). That means that the waves play a role in cell movement.

Furthermore, by observing pancreatic tumor cells under the electron microscope, they were the first to show that waves selectively round up half of the activated growth-promoting proteins available on the cell surface, form vesicles around them, and take them to the interior of the cell (Cancer Research, 2006. 66:3603-3610).

Epidermal Growth Factor (EGF) promotes growth through binding and activating its receptors, called Epidermal Growth Factor Receptors (EGFR). The finding is of interest because cancer is a disease of uncontrolled cell growth in which the normal balance between growth promotion and growth inhibition is disrupted. Many tumors exhibit elevated levels of EGFR, and activated EGFR have been implicated in the development and spread of several human cancers, including cancers of the colon, pancreas, ovary, breast and lung.

"Wave-based internalization of activated EGFR to the interior of the cell was a previously unknown mechanism," says Dr. McNiven.

Subsequent studies suggested that the formation of waves occur less often in certain tumor cells. It seems logical then, that cells that have fewer of these waves are bombarded with persistent signals that make them more likely to grow, move and invade (Cancer Research, 2006. 66(23):11094-6).

Everyday Excitement

"It is an exciting time to be a cell biologist," says McNiven. "Our understanding of basic cellular processes -- such as cell growth, death, migration, and signaling -- has increased so much over the past 10-15 years it is remarkable. It has also allowed us to gain a mechanistic understanding of human disease so we need to continue our expansion and investment in basic cell and molecular biology here at Mayo to keep us at discovery's edge."

-Yvonne Hubmayr, July 2008