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?
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