Cells are fantastic micromachineries, and researchers have traditionally had their hands full, studying their genetic makeup and how that relates to function and disease. Increasingly, however, researchers are seeing the bigger picture—how the environment and surrounding cells play an equally important role.
Mingming Wu, Biological and Environmental Engineering, has worked on a range of problems—from the migration of cancer cells, to the movement of sperm, to how algae proliferates. The common thread that runs through all of her projects is understanding how cells communicate with each other and their environment.
“We want to first understand from the mechanistic point of view, how cells talk to their environment and to each other and then come up with solutions to contemporary problems in health and the environment,” Wu says. “It’s like figuring out the language of cells, that’s what we do.”
In order to decipher the cells’ language, Wu and her team have created new technologies, tunable microfluidic devices that can mimic a cell’s environment in order to understand its behavior; and they have advanced imaging tools to analyze the cell’s behavior. “We build these small devices, comparable in size with the cell, and we can change the properties and measure the response of the cell under the microscope,” Wu says. “That has always been our approach, to develop engineering tools that allow us to do single-cell work that other techniques cannot do. We want to see the unseeable and measure the unmeasurable, that’s our motto.”
Creating a Microfluidic Device and a 3D Traction-Force Microscope to Study Breast Cancer Cell Communication
Understanding how cancer cells behave in their environment is a key effort of Wu’s lab. They started out investigating the chemical environment and how it affected breast cancer cells’ propensity to migrate.
To study this, they first created a microfluidic device where they could mimic the chemical signaling that occurs in the body. Importantly, they used a natively-derived material, made of collagen, that better mimics the complexity of real tissue. Using the device, they found that the same chemical signals the immune system uses to attract immune cells to a site can also attract cancer cells, promoting metastasis.
During these studies, Wu and her team also began to see that the physical environment—specifically the fluid flow and the stiffness of the extracellular matrix—had significant consequences on the migration of cancer cells. They developed a three-dimensional traction-force microscope, which could measure the interactions between cells and this matrix, using the same collagen-derived material. “This turned out to be quite difficult because these natively-derived materials are not like synthetic materials. They’re not easy to characterize, and they get modified by the cell,” Wu says.
With the persistence of PhD student Matthew Hall, now a postdoctorate at the University of Michigan, they were able to achieve it. “It was very gratifying when that happened. Many of our projects have great results, but none had been with so much effort,” Wu says. “We really needed to have the kind of persistence and ingenuity, the creative thinking to get that to work.” Another key aspect that contributed to the success of this project was the close collaboration with theorists Chung-Yuen Hui, Mechanical and Aerospace Engineering, and Vivek Shenoy at the University of Pennsylvania.
With this microscope, Wu and her team were able to see how cancer cells manipulate the matrix to enable their migration. “Basically the way the cells communicate with the matrix is by tugging on it,” Wu says. “It’s the force that’s the language between them. Before us, there was not a tool that can measure this force in three dimensions, in an actual biological matrix.”
By pulling on the matrix, the cell stiffens the matrix. This stiffening has the effect of aligning the fibers of the matrix, making it easier for the cancer cell to travel.
With the help of a new Research Project Grant (R01) from the National Institutes of Health, Wu and her team are now using another modification of their device to study how fluid flow plays a role in this process. “Our bodies are made up of 75 percent water, so there is flow everywhere,” Wu says. “In the vasculature, there is a fast flow of blood, and in the interstitial space there is slow flow; and we are interested in how things change in the presence of these different flows.”
These environmental factors have previously been overlooked, partly because there was no way to measure them. But they could be crucial in understanding the spread of cancer.
“Algal blooms are a huge problem now because of climate change and industrialization, especially in the U.S. and in China. The phenomena come from the sudden growth of one type of algal cells.”
“We have found cancer cells actually can morph from one type to another, if you subject it to different conditions, which in a way tells us why it is so hard to combat cancer. The cells are dynamic,” Wu says. “We have gathered a lot of information about how different signals, fluid flow, and the gel stiffness impact tumor cell invasion, so the question now is, how can we use this information to look at it from a systems level? This will be the next challenge for us, and this is where the excitement is going to be.”
Cell Communication and Algae Blooming
The devices Wu develops make her attracted to any problem having to do with cell-cell communication. Her attention was drawn to the problem of algal blooms when Lake Taihu, in her mother’s hometown of Wuxi, China, filled with harmful algae. With support from the USDA's National Institute of Food and Agriculture, Wu has been able to make contributions to address this threat.
“Algal blooms are a huge problem now because of climate change and industrialization, especially in the U.S. and in China. The phenomena come from the sudden growth of one type of algal cells. In our lab, we look at a type of cyanobacteria,” Wu says. “Our question is how does the cyanobacteria respond to the environmental cues? How does the cell-to-cell communication lead to the explosive growth of this bacteria?”
Wu and her team designed a device that can host tunable microhabitats, where they can study the different conditions under which the cyanobacteria proliferate. Along the way, with collaborator Stephan Winans, Microbiology and Immunology, they have detected quorum-sensing signals, a special class of molecules that help the bacteria work together to optimize their gene expression for maximal growth.
“Cells talk to each other through the secretion of this signal called a quorum signal,” Wu says. “We are now looking into whether the quorum sensing molecule is required for algae to bloom.”
While many researchers are looking for ways to address algal blooms, understanding what cellular processes cause them in the first place could lead to more sustainable and effective prevention. “In the long run, we really need to understand it to solve the problem,” Wu says.