Jan Liphardt is an Associate Professor of Bioengineering at Stanford University. He describes the work of the Stanford Physical Sciences-Oncology Center, where he is Principle Investigator.
Jan Liphardt: So we’re generally interested in the role of mechanics in cancer. And it has been known for a very long time that mechanics are important. In fact that's the basis of things like the breast self-exam where women look for hard lumps in their breasts. So, this is the kind of observation that has been very important clinically for a long time, but it has not been clear at all what the basic connections are between tissue mechanics on the one hand and the clinic on the other. That is exactly what we like to understand.
Pauline Davies: So in fact, when women do the self-exams and they’re looking for these hard lumps, are they actually looking for the growth of cancer cells or rather some hardening of the tissue surrounding what would be cancer cells?
Jan Liphardt: What they’re fundamentally looking for is a change of tissue mechanics. There are a large number of things that can alter tissue mechanics and some of them are related to cancer and others aren't and that's in fact one of the problems; just identification of regions of altered mechanics is only something that is occasionally connected to cancer and so there's a lot of research that has been done to understand that better. But if there is a cancer, typically what is observed is that in the relatively early stages of the disease, one observes a increase of overall tissue mechanics and then at later stages of the disease, the tissue can in fact even get softer. And part of that has to do with if the tumor is large enough the inside can become necrotic and very soft. So back to your general question, what is the actual hard object, is it the tumor cells or the tissue around the tumor cells? And a large part of that is the tissue around the tumor cells. It is how the growing tumor reorganizes the extracellular matrix in the normal tissue.
Pauline Davies: And where does that lead, what can be done about it?
Jan Liphardt: There are two kinds of questions on one can begin to address. Some of the questions have to do with improve detection, and diagnosis and risk stratification. What one would like to do is, based on better understanding of how mechanics is connected to disease, one would like to be able to go beyond if you have a lump in your breast you should go see your doctor. You would like to put the physician in a position to much more accurately and readily stratify these women according to the potential risk for the lump actually being malignant. So there are questions relating to early detection and diagnosis and risk stratification. Then there are other sets of questions relating to actual intervention or prevention. One thing that is interesting about tissue in general is that tissue mechanics change as we age and tissue mechanics change if we have other diseases. This means that if there is a connection between tissue mechanics and breast cancer, this means that we’re in a position to much better understand what potential connections are between aging and breast cancer and other diseases and breast cancer and that bears on prevention. And the final set of questions has to do with actual intervention. So what you do if you have a breast cancer? How on earth could it be useful to understand the connection between tissue mechanics and what on what will happen to the particular patient. The work that is most illuminating that regard has not yet been done in people, but only has been done in mice. The result there is quite clear. If you take a mouse and if you artificially, inappropriately harden the breast tissue and watch a cancer grow in this artificially hardened tissue, that tumor grows much more quickly and it metastasizes. If you take this model system and you chemically normalize tissue mechanics by using, for example, a small molecule, lysyl oxidase inhibitor, then the tumors no longer metastasize and they stay very small. So this is a direct proof that a small molecule intervention targeting tissue mechanics can be used to reduce the rate at which tumors grow and prevent their metastasis in this model system. There are many problems of course, and one of the problems is that it will, in general, be very difficult to give a broadband lysyl oxidase inhibitor to a person because collagen cross-linking is important for so many different things in the body; for your hearing, for your heart, for your tendons. And the real challenge now is not so much establishing that tissue mechanics are connected by cancer, but figuring out what to do about that. How does one specifically normalize tissue mechanics in a patient without broad side effects for many other things like the cardiovascular system and your hearing? So that means that the focus is now changing little bit from establishing the basic connections, to finding new ways of specifically normalizing abnormal tissue architecture’s in mechanics.
Pauline Davies: I guess you need some sort of drug that will stay in place.
Jan Liphardt: This is exactly right. So, if you think about normally what a small molecule drug does, it is targeted against a protein, for example, it is designed to turn a protein off. But, the target here is not necessarily specific protein; the target here is an abnormal architecture or abnormal mechanics, a different type of target then simply turning the enzyme on or off. So, not only does one have to think hard about how to localize the action of some drug to a particular region of the tissue, but also have it normalize architectures mechanics. That is an almost entirely unsolved problem right now.
Pauline Davies: Is that the sort of thing you’re also working on in your center?
Jan Liphardt: Well, exactly! So of course were interested on to go from equations to the patient. The more tractable area to do that in is in the area of early detection and diagnosis and risk stratification; but in the medium long-term, the major focus is actually is on intervention. What we think the real potential is in this area is that tissue mechanics seems to be very closely connected with the transition to invasive phenotype, with transition to metastasis. And that of course is the clinically, really central opportunity. However, there's also a potential problem because if what we’re doing is targeting transition to invasive phenotype and transition to metastasis, in some sense it may have to be a on pill that one takes every day for a long time. Because what you’re trying to do in some sense is to prevent the horse from running out of the barn, so you have to keep the door locked for a long time potentially. Once metastasis has begun, then it gets increasingly difficult to bring about the desired good outcomes. As you can tell it is, from the the intervention perspective, there are a lot of very significant unsolved problems that range from delivery and side effects, and how does one normalize abnormal mechanics, to what kind of therapies can we imagine that that may be some sort of low dose metastasis prevention therapies rather than what is done now, which is once you have metastatic disease then try to intervene. So a lot of unsolved problems.
Pauline Davies: You’ve just given a talk at the conference. Is there anything else that’s in that you haven't covered so far?
Jan Liphardt: Well we been emphasizing really the clinical view of what we've been doing but the insights we've been obtaining that may be important for the clinic, those have all come from very basic consideration of what might be going on in the tissues. They come from very basic physics motivated consideration of tensile stresses and elastic materials. And we were extremely lucky that some very old, simple equations governing the tensile stress in elastic materials, as a function of the shape of the materials, seem to be very powerful in predicting which mammary acini will transition to an invasive phenotype. So we were very lucky and now that we have that right physics framework it is much, much easier for us to design experiments that are really helpful in clarifying also the clinical picture.
Pauline Davies: I can see that what you’re doing could lead to an alternative approach for treating women who have cancer.
Jan Liphardt: Not only women, but for cancer in general, but that is true. On some level none of what were finding is that surprising from an evolutionary perspective or from the perspective of what are the fundamental requirements for multi-cellularity. The fundamental requirements for multi-cellularity are cells have to stick together and, if that's all they do that's not good, you will end up with a disorganized ball of cells. So not only do cells have to stick together, but they also have to stop dividing at the right time and that means that cells, once they’ve stuck together also need to invent mechanisms for knowing when to stop dividing. And those are typically referred to as, for example, in organ size control, this is something called Hippo pathway. And it is now clear that a lot of steps in cancer can be very closely related to very basic processes and mechanisms that are also at play in development that go right back to the basis of what cells need to do to form a multi-cellular organism. They need to stick together and know when to stop dividing at the right time. So, the expectation is that this viewpoint will be very powerful not only for breast cancer but other cancers. Yes targeting the mechanics of the extracellular matrix is certainly a relatively new and underexplored area.
Pauline Davies: Would this work have been done if it wasn’t for the PS-OC?
Jan Liphardt: No. I would still be doing exactly what I was what I was doing before which is grabbing individual DNA molecules with laser tweezers and pulling on them and I never literally would have never met Valerie.
Pauline Davies: Valerie Weaver?
Jan Liphardt: Yes, everyone knows her as Valerie. It is like Prince the singer - last name is not required! But it would not have been clear to me that there are such basic questions in cancer biology that are still unresolved. It's only the PS-OC program that has nucleated the whole process, and it is something I literally never would never have even considered - I would have not been aware that any of my training or experimental skills have any potential bearing on cancer.
Pauline Davies: And your work, bringing the physics perspective, has that been valuable to your co-workers in the PS-OC, the cancer researchers?
Jan Liphardt: Well, I think so but the jury is still out a little bit. So, it's literally taken us on 3 1/2 half years now to get to the point where all the bits and pieces are coming together. And what we have so far is a situation where there are very promising leads inspired by a physics viewpoint of the problem. And now is the time were we expect these tools and ideas and predictions to be increasingly incorporated into the day-to-day experiments that a cancer biologist would do. But that is really a second step. The first step was to develop the right kind of physical sciences based framework to think about these problems and that has taken a while.
Pauline Davies: Well thank you very much.