When cancer cells leave a tumor to migrate through the body, they embark on an arduous journey. They must move along narrow blood pathways and pass through different types of tissue by squeezing through openings smaller than cells. Most research on this migration has focused on its biological or biochemical aspects, but for Jan Lammerding, Biomedical Engineering, a key to ultimately beating cancer lies in understanding the mechanical processes the cancer cells go through.
How Do Breast Cancer Cells Move through the Body?
As part of the Center on the Physics of Cancer Metabolism, Lammerding leads a project exploring whether the physical properties of breast cancer cells determine how dangerous they are. “We know in cancer the problem isn’t the initial tumor,” Lammerding says.
“It’s when the cells from the tumor metastasize. They spread from the breast to the rest of the body—for example, the brain, the bones, or the liver. We’re asking research questions that get at the mechanical processes that allow the cells to spread. How much force does a cell need to generate to move through tissue? How large is the space it has to squeeze through and how much does it have to deform to get through that space? How does the process of squeezing a cell together affect its function?”
Lammerding’s lab creates microfluidic devices that mimic the physiological environment in tissues. Then the researchers observe cells moving through them. “We can control the material exactly,” Lammerding says. “We can set the stiffness of the material, the chemical composition, and the pore sizes. We know from measurements of tissues precisely how small and how large the pore sizes are that cells encounter.” Lammerding and his colleagues have observed cells trying to force their way through small openings, elongating themselves and deforming their nuclei to pass through. They have also seen cells give up and turn in another direction when a space is ultimately too narrow.
The Nucleus of a Cancer Cell: Its Key Role in Patient Survival
Lammerding’s main area of interest is the cell nucleus, the largest and most rigid organelle in the cell, which holds all the genomic information. The nucleus gets its rigidity from lamin A and lamin C, proteins that coat the inside of the organelle. “It seems that most aggressive breast cancers have less lamin A/C, so their nuclei are much more deformable, and they can pass through constrictions much faster,” Lammerding says.
“We have looked at biopsies from patients with breast cancer, and since we know which proteins make the nucleus rigid, we hope to be able to predict a patient’s risk for cancer recurrence, based on how much of the proteins they have,” explains Lammerding. “Our recent data show that patients with a high level of lamin A/C have rigid nuclei, and after removal of the tumor, they will go longer before recurrence of the cancer. Patients with low levels of the proteins, who have soft, squishy nuclei, have a much shorter rate of disease-free survival.”
The Lammerding Lab has also investigated the consequences to the cancer cell of having to squeeze through tight spaces. They observed the nuclei of cells rupturing, spilling some of their contents, as the cells passed through narrow openings. “Surprisingly, the cell is able to repair the nuclear envelope, repackage the contents, and survive, but the DNA may become damaged in the process,” Lammerding says.
“We were the first to show that just this physical process of migrating through tight spaces and rupturing can induce genomic instability and cause DNA damage,” says Lammerding. “The smaller the constriction, the more DNA damage in the cells, giving rise to mutations. Cancer cells not only arise from mutations, but they continue to acquire mutations over time. The more they acquire, the higher the genomic instability, and typically the more dangerous the cancer is and the more difficult to treat.”
“We were the first to show that just this physical process of migrating through tight spaces and rupturing can induce genomic instability and cause DNA damage.”
Forcing Cancer Cells to Kill Themselves
In another study, Lammerding and his coresearchers investigated the effectiveness of blocking some of the processes the cells use to repair their nuclear envelopes after rupture. Using drugs and genetic manipulation, they tried inhibiting DNA repair as well as repair of the nuclear envelope. Neither, alone, had much impact on the cancer cells. When they combined both treatments, approximately 60 to 70 percent of the cells died.
“The hope is that we can develop this into a therapy where the cancer cells essentially kill themselves by going through tight spaces,” Lammerding says. “When they split open, they can’t repair and they die.”
From Cancer to Muscle Disease: The Cells’ Mechanical Factor
Lammerding’s interest in the cell nucleus and the proteins within it tie his cancer work together with his other main area of research: how mutations to lamin A/C contribute to muscle disease phenotypes. At the latest count, over 500 different mutations in the gene encoding the lamin A/C proteins have been identified and most affect muscles, giving rise to diseases such as muscular dystrophy and heart disease. “Even though every cell in the human body has these lamin proteins, it appears that muscle cells are particularly sensitive to them,” Lammerding says. “The liver and the brain, for example, will have the same mutant proteins in them, but they will be perfectly fine while the muscles are affected. This suggests that there is a mechanical component to the disease condition because muscle tissue is under a lot of physical stress and the brain and liver are not.”
In an effort to gain insights into the mechanism behind these muscle diseases, the researchers took muscle cells from patients with muscular dystrophy and measured the stiffness of the nuclei. They found that the muscle cells from patients with muscular dystrophy were much more deformable and mechanically less stable. “Patients with these diseases have abnormal looking nuclei,” Lammerding explains. “They are much longer. They look like they’ve been stretched out. Under force their nuclei will deform a lot more, and their content can protrude outside the nucleus into the cell body— similar to what we saw in some of the cancer cells.”
How this deformation results in the disease is still under investigation. One theory Lammerding is pursuing says that the muscle cell recognizes severe damage to its nucleus. This triggers chemical signaling events that ultimately tell the cell to kill itself in a process known as apoptosis. While apoptosis is a DNA damage control common to most cells, the lamin mutation that renders the nucleus more sensitive to mechanical stress may cause nuclei in muscle cells to become increasingly damaged. This results in the loss of muscle fibers. “You have progressive cell death,” Lammerding says. “Mechanical damage may be only one aspect of the disease. Right now, we’re trying to understand how much it contributes.”