Physics & Cancer Blog

Creating the Field of the “Physics of Cancer”

A recent review paper on metastatic spread brings to the fore one of the most important questions that needs to be addressed in the creation of a physics of cancer. The basic issue is, why do the cells in the primary tumor develop the genetic and epigenetic properties that enable them to migrate through the body and establish successful (from the tumor’s perspective) metastatic outposts. It is hard to believe that these properties are selected for by direct evolutionary pressure, as the probability of success is extremely small and cells acting independently would have a huge advantage if they just stayed put. An answer to this puzzle could inform treatments that deter metastatic spread, which after all is the cause of death in a vast majority of cases.

Before proceeding to possible resolutions, it is important to point out that metastatic growth seems to be difficult even for cells that have already done it once. One can take cells from a metastasis and implant them into fresh tissue (in a mouse model, of course) and determine the rate of successful colonization. One can then repeat the process several times to enrich for growth potential. It seems that even these cells can form secondary tumors with low probability (perhaps 1%). So, whatever the final bottleneck is in metastatic inefficiency, it does not appear that one can totally eliminate it by direct selection.

The simplest proposition to explain these observations would be to combine random genetic variation with the need for a minimum size of nucleation for tumors. The idea here is that as the primary tumor becomes more and more genetically unstable, clones emerge that are motile and that have a much reduced nucleation barrier. Exactly how long this would take to occur is impossible to estimate given our ignorance regarding the mapping from genotype to phenotype. This scenario could explain examples where cells leave the primary tumor quite early on (it is undoubtedly easier to turn on motility) but fail to establish metastases until much later. This delay could just be a numbers game (as the primary tumor grows, more cells are released increasing the cumulative odds) but surmounting an exponential barrier is usually accomplished by lowering the barrier, not increasing the prefactor. This concept does not explain why the barrier cannot become zero for the proper clone. It may be that colonization happens occurs before that (due to the large prefactor) and hence the cells never get a chance to become fully capable or it may be that a majority of the cells switch out of the capable state once growth begins; this is similar to differentiation of normal stem cells, and only the residual “cancer stem cells” are sill colonization-capable. This could be tested by attempt to enhance the percentage via selection based on stem-cell markers.

A different conceptual approach is taken by Norton and co-workers, with related work by Carlos Maley. In their formulation, cells are selected for migratory properties so as to help the primary tumor grow more efficiently. This motility may allow both for local motion and for what has been called self-seeding, namely that cells actually leave the tumor, circulate through the blood and lymph systems, and return back to the same tumor. Some evidence for this has been presented, again of course in a mouse model. It seems to me that this approach may help explain the motility transition but does nit really address why these cells can colonize foreign tissues; this again appears to be left to chance genetic changes of these now motile cells, changes that presumably are not needed to reattach to the primary tumor. This could all be investigated experimentally, bu has not yet been done so.

A last speculative idea returns to the notion of differentiation, but now within the context of the primary tumor. There are many cases in biology in which intercellular signaling maintains a small subpopulation of cells in a state which makes no sense from a purely individualistic perspective. One well-=known example is that of the persister phenotype in E. Coli, which have greatly diminished growth so as to provide an advantage to the colony as a whole. Tumors might create a reservoir of seeding cells (with both migratory and colonization capabilities) as insurance against environmental disaster; these cells would have some characteristics of stem cells, but need not be a fixed subpopulation. This idea meshes with the previous explanation for why the typical cells in a metastasis are  not very colonization-capable, but many, many questions remain. The role of genetic versus epigenetic degrees of freedom is obscure; cancer cells seem to make much more use of genetic variation than do, for example, bacterial colonies. It is less obvious how to explain “metastatic tropism” (the strong correlation between primary tumor site and metastasis location); in the nucleation picture, one can easily imagine a barrier that varies with target tissue type. Perhaps even the maintained seeding cells are not equally well-matched to alternate sites for spread, and probably even these cells have some sort of growth barrier to surmount.

It is our job as physicists to connect these conceptual pictures with doable experimental tests. It is only then that we can truly be on the road to creating the field of the “physics of cancer”.

The Physics of Cancer – Food for Thought

The Physics of Living Systems Community has collectively become excited at the possibility of contributing to a better understanding of cancer. The signs of this are manifold. There is a workshop scheduled next spring at the KITP in Santa Barbara on the Physics and Mathematics of Cancer, co-organized by physicists and by cancer biologists. There is a tutorial on Sunday at the upcoming American Physical Society March meeting in Boston to introduce this subject to interested attendees. There is a special issue of the journal Physical Biology (Vol 8.,No. 1 in 2011) devoted to research at the National Cancer Institute sponsored Physical Science Oncology Centers. And, we here at the Center for Theoretical Biological Physics will be starting a new synergy research area devoted to this topic.

So, what gives? I think the answer here lies in the fact that physical science can offer both tools and concepts that could help deal with the amazing complex story of cancer as it has become to be understood. Aside from some special cases, attempting to cure cancer by following the simple path of finding a single defect (perhaps one key mutation leading to constitutive activity of a signaling protein) and then devising a small molecule therapy just has not proven to be a powerful enough strategy. In fact, cancers often respond to such treatment with short-term retraction followed inexorably by long-term renewed vigor. This defeat of therapy can occur by a variety of individual cell changes (resistance mutations for example), by collective changes within the entire tumor, by recruitment of surrounding normal cells; the details are sorely absent. Surely coupled to this is the fact that cancers are remarkably heterogeneous in their genomic profiles and in their physical manifestations; there are many redundant pathways leading to similar dire consequences. We as a society are thus faced with the prospect of pending hundreds of thousands of dollars per patient on drugs that increase life expectancy by merely a few months. It may be the height of hubris to think that physicists can make progress on topics that have resisted the best efforts of the oncology community, but there is certainly a strong motivation to try.

And, there are good intellectual reasons as well to work on cancer. Cancer touches on some of the most basic questions underlying biology, related to the plasticity of genetic degrees of freedom, the nature of cell differentiation, the constraints that multi-cellularity places on the proliferation and selfish behavior of individual cells, the role of environment in both genotypic selection and phenotypic behavior etc. There is room here for working on evolutionary dynamics, on genetic systems that control cell fate, on the mechanics of cell motility, on high-resolution imaging inside the human body, and on the design of drug delivery systems. So, as you ponder where you can make your own personal contributions to the Physics of Living Systems, do not overlook the possibility of working on the physics of cancer; it is one of the true challenges of our time.

Prof Herbert Levine, Rice University

Key Questions asked by Cancer Researchers at 11/10 Physics of Cancer Metastasis Workshop

A list of physics and cancer research challenges compiled by Lalit Patel at the University of Michigan from the attendees of the NSF Physics of Cancer Metastasis workshop held in Arlington, VA in November 2010.

The Physics of Cancer Metastasis meeting brought together scientists in both the physical sciences as well as the biological sciences with the intent of spawning an interdisciplinary dialogue regarding the unresolved questions in metastatic tumor biology. The conference agenda ended with an open discussion in which attendees were asked to identify two-to-three “Holy Grails” –  questions that if tackled in an interdisciplinary manner could lead to fundamental advances in our understanding of metastatic cancer. The ideas discussed were diverse but fell into distinct categories.

Modeling Disease
The following ideas and challenges were mentioned with respect to quantitative modeling:
  • Using population genetics and evolutionary game theory to parameterize patterns of progression
  • Models that predict the minimum number of mutations and the temporal order of mutations that confer a metastatic vs local phenotype
  • Developing readouts for mathematical models that can be validated using clinical observation
  • Modeling requires a sense of scale. Molecular events happen on a very different space and time scale than cell trafficking or tissue microstructure changes.
  • Quantitative models of tissue patterning that is inclusive of physical and biological factors
  •  The following ideas were mentioned with respect to experimental models:
  • T and B cells undergo genetic translocation, have memory behavior, demonstrate tissue invasiveness, are bone and lymph homing, and do not demonstrate anoikis. The biology of lymphocytes may be a model for metastatic processes in cancer
  • Identifying the simplest creature that develops cancer may help get past the complexity of human tumors and allow investigation into the essentials/fundamentals of cancer
Observing Disease
The group’s interest in direct observation of clinical disease was motivated as much by discussions of metastasis biology as by a desire to obtain data needed to validate quantitative models. In some cases specific technological advances were suggested. In other cases the type of observational data desired was identified while leaving the modality of observation open. The specific ideas mentioned were:
  • Quantitative observation of cells entering circulation at primary tumor site and leaving at metastatic site for temporal analysis, validation of quantitative models, and hypothesis formation regarding mechanisms of dissemination and invasion
  • Using liquid biopsies and temporal analysis for probability distributions for where, in which patients, and over what period of time cells disseminate to different sites
  • Developing imaging techniques distinguishing “hot” tumors from boring ones
  • In vivo metabolic rates
  • Coupling tissue structure observation with pattern recognition for prediction
  • Cytometry in situ of primary tumor, blood, and secondary tissues to observe cells leave, which ones stay in the blood, and which invaded
  • Sensors for where cells move through the body to enable temporal observational studies
  • Imaging technology that permits microstructure observation perhaps
  • Using secondary harmonics and magnetic spectroscopy to observe tissue-scale interactions with disseminated cancer
  • Imaging technology that is sensitive enough to image rare cells like CTCs and DTCs
  • Some genetic anomalies are more interesting than others – how do we observe the emergence of these anomalies in situ?
  • Observation of dormant micrometasases to get at the question of whether it is mass dormancy (death rate = birth rate) or if it is cellular dormancy (birth rate = 0 and death rate = 0)
  • Clinical observation of difference in epigenetic/gentetic state of primary vs metastatic tumors and its association with difference in proliferation rate between primary vs metastatic tumors
  • We know its faster, but how much faster?
  • What is the genetic basis of faster?
  • Is the driver of changes in proliferative behavior genetic or epigenetic?
  • Include observations of tissue structure difference to see if it could be the microenvironment
  • In vivo sensors of tissue structure and forces
The Physical Biology of Disease
Some of the most creative ideas discussed centered on the applications of mechanobiology to metastasis. There was also discussion on the application of thermodynamics to understanding metastatic cancer cell biology. In both spaces there were more questions than answers. They include:
  • What is the role of cell and tissue scale forces in cancer cell’s spreading, seeding, and remodeling  secondary sites
  • Is cancer pushed out of the primary tumor site? Does it crawl out? Is it passively let out? How can we target the processes associated with each of these models of cancer-cell-ejection to minimize metastatic spread?
  • What physical attributes distinguish cells that stay in the primary site versus cells that leave? Is it “stickiness”? If so can we keep them from unsticking? Or is it motility and can we reduce their motility?
  • “Capture Therapy”
  • Assuming that its stickiness can we trap cancer cells from circulation by making a specifically sticky fake secondary environment to prevent them from seeding new tumors?
  • If so what physical and chemical attributes would make for a good trap?
  • Will require biology, quantitiative modeling, and clinical observation to accomplish this goal
  • Thermodynamics of disease
  • What energy utilization efficiency differences exist between “hot” vs “boring” cancer?
  • Can we formalize the Warburg effect?
  • Metabolism differences are already used for imaging, but is there something about energy utilization that can be targeted for treatment?
  • How does cancer affect the mechnobiology and microstructure of the tissue it resides in?
  • Changes in vessel (vascular and lymphatic) permeability
  • Interstitial pressure changes
  • Changes in transport processes defining gradients and patterns of chemotaxis?
  • Biological and clinical consequences of these changes?
  • Can we build a bridge between the mechanobiology and the molecular biology of disease?
  • The biologists framed their ideas in genetic and epigenetic terms.
  • The physicists discussed forces-transduction, tissue structure, cell shape, motility
  • Ingber’s talk demonstrated the beginnings of a bridge between the two with evidence of gene-expression attractor states being adopted in response to mechanical stimuli
  • Can we complete this bridge by delineating how cells translate mechanical stimuli lead into changes in molecular phenotype?


We are pleased to launch the Physics and Cancer website in hopes that it will become a useful resource in the advancement of the contribution of physics to cancer research.

Eshel Ben Jacob, University of Tel Aviv
Krastan Blagoev, National Science Foundation
Herb Levine, Rice University

Cancer Researchers Need…

An Invitation to Cancer Researchers

Cancer Researchers Need… is a blog where questions and problems that cancer researchers come across can be posted for the physics community to address.