by Jackie Swift
The history of science is full of breakthroughs made possible by the creation of new technologies. Imaging, in particular, has been fundamental to the pursuit of biomedical knowledge. From microscopes to x-rays to ultrasound, these tools opened up a world of research possibility.
“Imaging and microscopy have played key roles in facilitating scientific discoveries,” says Steven G. Adie, Meinig School of Biomedical Engineering at Cornell University, whose lab focuses on developing new imaging tools. “I’m excited about working in this area because expanding imaging capabilities and the information we have access to is going to lead to new discoveries, new ways of diagnosing diseases, and new treatments.”
The Biophysical Forces of Cancer Metastasis
Adie has taken his groundbreaking optical imaging techniques and applied them to an array of projects. Some of the most notable are related to cancer. Collaborating with Claudia Fischbach-Teschl, Meinig School of Biomedical Engineering, and her lab, the researchers of the Adie group have turned their attention to the study of biophysical forces, known as cellular traction forces (CTFs), involved in cancer metastasis.
“Cancer cell metastasis is not a passive process where the cells simply diffuse into blood vessels and end up in other parts of the body,” Adie says. “It’s more an active migration, an invasion. Cancer cells squeeze themselves through the extracellular matrix (ECM). They pull themselves along and force their way into blood vessels.”
The ECM is a network of extracellular macromolecules such as collagen, enzymes, and glycoproteins that provide structural and biochemical support for cells. Cancer cells are known to deform and often digest the collagen in order to force their way through and into blood vessels, which they use to travel to other parts of the body. When they arrive at their destination, they force their way out again to seed a metastatic tumor. “The early stages of cancer metastasis involve these biophysical factors, and we’ve developed a way to image these interactions in physiologically-relevant 3D cell cultures as a function of time,” Adie says.
“Let’s say that mechanical properties are the first things to change before cancer cells start invading tissue…and we can image these changes.”
As their baseline imaging platform, the Adie group uses optical coherence tomography (OCT), which utilizes an interferometer to detect small differences in the time-of-flight of light waves — somewhat like an optical version of ultrasound. They combined OCT with traction force microscopy, a family of methods used to quantify CTFs, ultimately creating a new imaging technique known as traction force optical coherence microscopy (TF-OCM).
“We started by imaging a simple biological system where we have isolated cells migrating around,” Adie explains. “We can take those cell–induced deformations of the ECM and reconstruct quantitatively the CTFs involved. This allows us to study, in isolated cell settings, how the forces of a cancer cell are different from those of a noncancerous cell.”
Seeing Interactions among Thousands of Cells, from Minutes to Days
The researchers are now transitioning their technique to tumor spheroids created by the Fischbach-Teschl group. “These are more biologically relevant settings,” says Adie. “You might have thousands of cells in a tumor spheroid. How do these cells apply forces and what are the forces involved in cancer cell migration when you have thousands of cells working together?”
Since OCT detects oscillations in the optical wave, thus capturing the full optical field, it allows Adie and his collaborators to form images after they’ve acquired data. This access to the full optical field allows them to reconstruct three dimensional images where all depths are equally in focus without actually shifting the focus to each depth. “We can now do large-scale volumetric imaging of biophysical factors in 3D cell cultures with improved temporal resolution, allowing us to see dynamic interactions on timescales spanning minutes to days,” Adie says. “It’s a capability that hasn’t existed in the field until now.”
Capturing Mechanical Properties in Full Volumes
Continuing to build on his optical imaging techniques, Adie realized researchers needed a better way to image mechanical properties in cells and three-dimensional cell constructs, so the Adie group developed another new technique called photonic force optical coherence elastography (PF-OCE). “Before we came along, the typical way to do high-resolution imaging of mechanical properties in these viscoelastic biological media was to use atomic force microscopy, where you tap the surface of the sample and get information about the properties of the surface,” Adie explains. “But we wanted to image those properties in full volumes because we know that the mechanical properties of the three-dimensional matrix the cells are in can play a really important role in whether or not cancer cells metastasize.”
PF-OCE combines OCT detection with a weakly focused laser beam that pushes on microscopic beads embedded in the ECM of engineered biological systems. This causes small displacements that depend on local mechanical properties of the matrix around each bead. “We have a pushing beam that’s aligned with an OCT detection beam, and we just scan both through the sample,” Adie explains. He is collaborating again with Fischbach-Teschl on the combined application of PF-OCE and TF-OCM to cancer research, and he is working with another colleague, Ben D. Cosgrove, Meinig School of Biomedical Engineering, who studies muscle stem cell mechanobiology.
Imaging the Interplay between the Mechanical Properties of the Extracellular Matrix and Cell Behavior
“We want to correlate how the mechanical properties in the ECM influence cell behavior and how the cells also modify the properties of the ECM,” Adie says. Understanding this has relevance to cancer migration, but beyond that, Adie points out, the technique can also help researchers unlock the mysteries of stem cell behavior — how their function is tied in with these mechanical factors, and how these factors also play a part in processes like embryo development and wound healing.
Adie hopes to see his imaging techniques have clinical impact in the future as they help bring to light more discoveries about the biomechanical properties of tissue. “I’m going to hypothesize that we will make a discovery,” he says. “Let’s say that mechanical properties are the first things to change before cancer cells start invading tissue. Let’s say someone has skin lesions and we can image these changes in the mechanical properties of the tissue. That could be an early biomarker before the lesions turn cancerous, a way to catch cancers early. And that would be really exciting, right?”