*** UPDATE: Registration has been extended to September 19, 2012, 5:00 pm Pacific Time. ***
The NCI-funded, Physical Sciences in Oncology Center (PSOC) at USC is hosting its second annual symposium on interdisciplinary cancer research on September 27, 2012 from 7 am to 6 pm. The event is free but registration is required.
The symposium will include a great diversity of expertise, spanning cell analysis, cancer evolution, modeling, drug delivery, and therapeutic response. We also have two fascinating keynote speakers: David A. Kirby, author of Lab Coats in Hollywood, and Corby Kummer, senior editor and acclaimed food critic for the Atlantic Monthly. Here’s the confirmed lineup:
Eun Sok Kim (University of Southern California)
Cagri Savran (Purdue University)
Paul Newton (University of Southern California, and Co-Director of CICO)
Paul M. Kulesa (Stowers Institute)
It should be a wonderful event, and I hope you can attend!
You can find the full flyer and description here.
You can find the agenda here.
On May 18th, Paul Newton and I received received significant startup funding from the USC James H. Zumberge Research and Innovation Fund to establish the Consortium for Integrative Computational Oncology (CICO). We’re grateful for this opportunity to build a new resource for USC and the broader cancer community!
CICO seeks to develop and promote cross-disciplinary, integrative collaborations across the USC (particularly the Viterbi School of Engineering and the Keck School of Medicine) in clinically-oriented cancer modeling. Among our guiding principles:
- Computational modeling of cancer must be driven by clinical needs. Modelers need to work hand-in-hand with clinicians at all steps of the modeling process.
- Computational oncology works at its fullest potential when working with clinical data. This focus:
- drives advances in mathematical model design,
- allows us to evaluate and choose between competing models,
- helps biologists to test, validate, and refine current cancer biology orthodoxy,
- helps clinicians to better interpret their data, and
- is most likely to lead to computational tools that will make an impact in the clinic.
- Integrative computational oncology holds the potential to integrate advances from mathematical modeling, experiments, and clinical data into comprehensive tools that give a better understanding of cancer than any of these individual pieces alone.
- Integrative computational oncology must include student education at its core, to create a true “ecosystem” of clinically-focused modeling students from the undergraduate to postdoctoral level.
You’ll be hearing a lot more about CICO as we ramp up in the coming year!
Today, Paul Newton and I submitted a joint grant to the National Science Foundation in the Physical and Engineering Sciences in Oncology (PESO) program. PESO is a neat program jointly run by the NSF and NCI, that has spun off the NCI’s recent physical sciences approach to cancer. Our proposal brings together a a variety of techniques (spanning agent-based models, signaling, tissue biomechanics, fluid flow, nonlinear transport, and Markov chains) to study targeted aspects of cancer metastasis, from early microinvasion to circulating tumor cells (CTCs) to whole-body dissemination of metastatic disease.
On a personal note, this is my first proposal as a Co-PI. *fingers crossed*
For those of you in the neighborhood, I’ll be giving a on patient-calibrated computational modeling of breast cancer, and on the role of mathematical modeling in facilitating a deeper understanding of pathology and mammography.
Monday, February 6, Center for the Applied Mathematical Sciences (CAMS) at the University of Southern California.
Link and abstract: http://cams.usc.edu/Colloquia/2-6-2012.html
I am pleased to report that our paper has now been accepted. You can download the accepted preprint here. We also have a lot of supplementary material, including simulation movies, simulation datasets (for 0, 15, 30, adn 45 days of growth), and open source C++ code for postprocessing and visualization.
I discussed the results in detail here, but here’s the short version:
- We use a mechanistic, agent-based model of individual cancer cells growing in a duct. Cells are moved by adhesive and repulsive forces exchanged with other cells and the basement membrane. Cell phenotype is controlled by stochastic processes.
- We constrained all parameter expected to be relatively independent of patients by a careful analysis of the experimental biological and clinical literature.
- We developed the very first patient-specific calibration method, using clinically-accessible pathology. This is a key point in future patient-tailored predictions and surgical/therapeutic planning.
- The model made numerous quantitative predictions, such as:
- The tumor grows at a constant rate, between 7 to 10 mm/year. This is right in the middle of the range reported in the clinic.
- The tumor’s size in mammgraphy is linearly correlated with the post-surgical pathology size. When we linearly extrapolate our correlation across two orders of magnitude, it goes right through the middle of a cluster of 87 clinical data points.
- The tumor necrotic core has an age structuring: with oldest, calcified material in the center, and newest, most intact necrotic cells at the outer edge.
- The appearance of a “typical” DCIS duct cross-section varies with distance from the leading edge; all types of cross-sections predicted by our model are observed in patient pathology.
- The model also gave new insight on the underlying biology of breast cancer, such as:
- The split between the viable rim and necrotic core (observed almost universally in pathology) is not just an artifact, but an actual biomechanical effect from fast necrotic cell lysis.
- The constant rate of tumor growth arises from the biomechanical stress relief provided by lysing necrotic cells. This points to the critical role of intracellular and intra-tumoral water transport in determining the qualitative and quantitative behavior of tumors.
- Pyknosis (nuclear degradation in necrotic cells), must occur at a time scale between that of cell lysis (on the order of hours) and cell calcification (on the order of weeks).
- The current model cannot explain the full spectrum of calcification types; other biophysics, such as degradation over a long, 1-2 month time scale, must be at play.
I just posted a job opportunity for a postdoctoral researcher for computational modeling of breast, prostate, and metastatic cancer, with a heavy emphasis on calibrating (and validating!) to in vitro, in vivo, and clinical data.
If you’re a talented computational modeler and have a passion for applying mathematics to make a difference in clinical care, please read the job posting and apply!
(Note: Interested students in the Los Angeles/Orange County area may want to attend my applied math seminar talk at UCI next week to learn more about this work.)
The Macklin Math Cancer Lab is pleased to welcome Gianluca D’Antonio, a M.S. student of Luigi Preziosi and mathematician from Politecnico di Torino. Gianluca, who brings with him a wealth of expertise in biomechanics modeling, will spend 6 months at CAMM at the Keck School of Medicine of USC to model basement membrane deformation by growing tumors, biomechanical feedback between the stroma and growing tumors, and related problems. Gianluca’s interests and expertise fit very nicely into our broader vision of mechanistic cancer modeling, as well as USC / CAMM’s focus on applying the physical sciences to cancer (as part of the USC-led PSOC).
He is our first international visiting scholar, and we’re very excited for the multidisciplinary work we will accomplish together! So, please join us in welcoming Gianluca!
Next Monday (October 17, 2011), the USC-led Physical Sciences Oncology Center / CAMM will host a short course on multidisciplinary cancer modeling, combining the expertise of biologists, oncologists, and physical scientists. I’ll attach a PDF flyer of the schedule below. I am giving a talk during “Session II – The Physicist Perspective on Cancer.” I will focus on tailoring mathematical models from the ground up to clinical data from individual patients, with an emphasis on using computational models to make testable clinical predictions, and using these models a platforms to generate hypotheses on cancer biology.
The response to our short course has been overwhelming (in a good way), with around 200 registrants! So, registration is unfortunately closed at this time. However, the talks will be broadcast live via a webcast. The link and login details are in the PDF below. I hope to see you there! — Paul
7:00 am – 8:25 am : Registration, breakfast, and opening comments, etc.
David B. Agus, M.D. (Director of USC CAMM)
W. Daniel Hillis, Ph.D. (PI of USC PSOC, Applied Minds)
Larry A. Nagahara (NCI PSOC Program Director)
8:30 am – 10:15 am : Session I – Cancer Biology and the Cancer Genome
Paul Mischel, UCLA – The Biology of Cancer from Cell to Patient, Oncogenesis to Therapeutic Response
Matteo Pellegrini, UCLA – Evolution in Cancer
Mitchelll Gross, USC – Historical Perspective on Cancer Diagnosis and Treatment
10:30 am – 12:15 pm : Session II – The Physicist Perspective on Cancer
Dan Ruderman, USC – Cancer as a Multi-scale Problem
Paul Macklin, USC – Computational Models of Cancer Growth
Tom Tombrello, Cal-Tech – Perspective: Big Problems in Physics vs. Cancer
1:45 pm. – 3:10 pm : Session III – Novel Measurement Platforms & Data Management & Integration
Michelle Povinelli, USC – The Role of Novel Microdevices in Dissecting Cellular Phenomena
Carl Kesselman, USC – Data Management & Integration Challenges in Interdisciplinary Studies
3:10 pm – 3:40 pm : Session IV – Creativity in Research at the Interface between the Life and Physical Sciences
‘Fireside Chat’ David Agus and Danny Hillis, USC
4:00 pm – 5:00 pm : Capstone – Keynote Speaker
Tim Walsh, Game Inventor, Keynote Speaker
5:30 pm – 8:00 pm : Poster Session and Reception
After a lot of revision, I have merged my two papers on ductal carcinoma in situ (DCIS) in to a single manuscript and resubmitted to the Journal of Theoretical Biology for final review. A preprint is posted at my website, along with considerable supplementary material (data sets and source code, and animations). Thanks to my co-authors and other friends for all the help in the revisions. Thanks also the reviewers for insightful comments. I think this revised manuscript is all the better for it.
DCIS is a precursor to invasive breast cancer, and it is generally detected by annual mammographic screening. More advanced DCIS (with greater risk) tends to have comedonecrosis–a type of cell death that leaves calcium phosphate deposits in the centers of the ducts. In fact, this is generally what’s detected in mammograms. DCIS is usually surgically removed by cutting out a small ball of tissue around what’s found in the mammograms (breast-conserving surgery, or lumpectomy). But current planning isn’t so great. Even with the state-of-the-art in patient imaging and surgical planning, about 20%-50% of women need to get a second surgery because the first one didn’t get the entire tumor.
So, there’s great need to understand calcifications, and how what you see in mammography relates to the actual tumor size and shape. And if you do have a model to do this, there’s great need to calibrate it to patient pathology data (the stuff you get from your biopsies) so that the models say something meaningful about individual patients. And there has been no method to do that. Until now.
(As far as I know), this paper is the first to calibrate to individual patient immunohistochemistry and histopathology. This, along with some parameter estimates to the theoretical and experimental biology literature, allows us to fully constrain the model. No free parameters to play with until it looks right. Any results are fully emergent from a mechanistic model and realistic parameter estimates rooted in the biology.
This model also includes the most detailed description of necrosis–the type of cell death that results in the comedonecrosis seen in mammograms. We include cell swelling, cell bursting, gradual loss of fluid, and the very first model of calcification.
Clinical predictions, with lots of validation:
All said and done, the model gives some big (and validated!) predictions:
- The model predicts that a tumor grows through the duct at a constant rate. This is consistent with what’s actually seen in mammography.
- The model gives a new explanation for the known trend: when necrotic cells burst and lose fluid, it makes it more mechanically favorable for proliferating cells to push into the center of the duct, rather than along the duct. For this reason the model predicts faster growth in smaller ducts, and slower growth in larger ducts.
- The model predicts growth rates between 7.5 and 10 mm per year. This is quantitatively consistent with published values in the clinical literature.
- The model predicts the difference between the size in a mammogram and the actual size (as measured by a pathologist after surgery) grows in time. This unfortunately means that it’s unlikely that there is some “fixed” safe distance to cut around the mammographic findings.
- On the other hand, the model predicts that there is a linear correlation between the size in a mammogram and the actual (pathology) tumor size. This bodes well for future surgical planning.
- Better still, the linear correlation we found quantitatively fits through 87 published patients, spanning two orders of magnitude.
New insights on DCIS biology:
The model also makes several key predictions on the smaller-scale biology:
- The model predicts that fast swelling of necrotic cells (on the order of 6 hours) is responsible for the tear between the viable rim and necrotic core seen in just about every pathology image of DCIS.
- The model predicts that the necrotic core is “age structured”, with newly necrotic cells (with relatively intact nuclei) on the outer edge, and interior band of mostly degraded but noncalcified cells, and a central core of oldest, calcified material. This compares well with patient histopathology.
- Comparing the model-predicted age structuring to histopathology predicts a sharper estimate on the various necrosis time scales: swelling and lysis (~6 h) < slow fluid loss (~days to a week) < pyknosis (~10+ days) < calcification (~2 weeks).
- Because the model only predicts linear / casting-type calcifications (long “plugs” of calcification), other biophysics must be responsible for the variety of calcification types seen in mammography.
- Among other mechanisms, we postulate a very long-timescale (1-2 months) process of degradation of the phospholipid “backbone” of the calcifications, resulting in degradation of the calcifications. The cracks seen in the central portions of calcifications (in histopathology) supports this view.
This last point is interesting: only 30-50% of solid-type DCIS has linear calcifications. This could provide an explanation for that, and may help improve the accuracy of diagnostic mammography. Furthermore, it may explain spontaneous resolution: where calcifications sometimes disappear from mammograms, while the underlying tumor is still present.
Long-term outlook, and next steps:
In this work, we have taken a step towards moving mathematical models from the blackboard to the clinic. We actually can calibrate models to individual patient data. We actually can make testable predictions on things like growth rates and mammography sizes.
The next step is to start validating the predictions in individual patients, rather than by the clinical literature. Our team has started doing just that. Our pathologists are getting histopathology measurements from several patients. Our mammographer is giving us calcification sizes and other data from 2 time points for each patient. This will allow us to validate the predicted growth rate in each patient!
In the longer term, I’d like to use the model to develop a spatial mapping between the calcification appearance in the mammogram and its actual shape in the breast, as an improved surgical planning tool. I’d like to study the impact of inadequate surgical margins in our simulated tumors. And I’d like to expand the model to the next natural (and significant!) step of microinvasion, and progression to full invasive ductal carcinoma.
We’ve taken some nice baby steps towards making an impact in the clinic. And that’s what this modeling is all about.