That's the subject you've chosen to pursue in your own lab?
I was hired at UPenn as part of what was going to be a big interdisciplinary cancer research group. But shortly after I got there the University had a funding crisis and stopped hiring. It ended up that I was the only cancer researcher in what was really an engineering and physics group. I couldn't get graduate students to come over because they were terrified by all the physics and engineering, and the lab was way on the other side of campus from the biological sciences labs. So I hired a technician, Nastaran Zahir, and trained her in lab work, hoping that she might stay to do grad school—and she did.
I was trying to think of a project for Nas that was relevant to my interests and to engineering. To make a long story short, I started wondering about things like viscoelasticity and whether that might impact tumor behavior in a 3D environment. We started thinking about when the mammary acinus expands during development or during tumor progression. Could there be some kind of physical force that's altered, and could we model it?
But I couldn't get any money for these studies. No one would take a chance on a grant for this; it just sounded too crazy. We ended up going around, collecting other peoples’ extra mice—mice with myc- or ras-based tumors or whatever—to see if we could make force measurements on them. And what we found was that breast tumors are stiffer than normal tissue. We've been expanding on that ever since.
How does stiffness in the tumor environment impact cancer cells’ behavior?
A 3D reconstruction showing how membrane surface topology changes in cancerous cells.
Think of it this way. Mammals start off as one little egg, which is very soft and is not under tension. As an animal develops different tissue types, these different tissues have different properties of stiffness or softness, and the cells in them tune themselves to the stiffness of the extracellular matrix in their environment. They do this, in part, through ion channel activation but also through clustering of integrins. This changes the activation of Rho GTPases, which in turn alters actomyosin contractility and actin behavior. That then feeds back and changes how receptors function (by affecting their clustering or localization), which then drives reorientation of matrix bundles and more deposition, stiffening the local environment. You can therefore drive different configurations of cell surface receptors—literally reprogram the cell—simply by changing the stiffness of the cell's environment.
When you talk about a breast tumor, or other tumors we work on like pancreatic or brain tumors, they don't have to stiffen very much to become a tumor. Tumor cells are hypersensitive to stiffness changes because many oncogenes change the cell's actomyosin contractility. We're also finding that oncogenes change things like the glycocalyx and cell surface glycoproteins, which can also affect the cell's mechanical characteristics. We can actually use atomic force microscopy and fluorescence image contrast (FLIC) microscopy to measure some of these changes.
I'm excited about how things are turning out. I love where our work is going, and I think people are finally starting to pick up on how interesting this stuff is. Of course, we have a long way to go. But I have a nice group and I feel extremely privileged to be part of this.