DCIS modeling paper accepted
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.