An agent-based model with ECM to study the mechanics of DCIS microinvasions

AnaForero Pinto

Moffitt Cancer Center/ University of South Florida

"An agent-based model with ECM to study the mechanics of DCIS microinvasions"

Microinvasions in ductal carcinoma in situ (DCIS) are malignant cells that have broken through the basement membrane (BM) and extend into the stroma with no focus larger than 1 mm. Since microinvasions constitute the first step in the metastatic cascade, identifying the causes of microinvasions will help distinguish between progressors or non-progressors among the DCIS patients, thus improving treatment. The mechanical tumor-stroma interactions play an important role in this process. Studies have shown that elevated collagen stiffening, deposition, and fibril crosslinking are correlated with tumor aggressiveness and invasion in breast cancer. Therefore, here we present SilicoDCIS, a 2D off-lattice center-based agent-based model (ABM) of ductal carcinoma in situ (DCIS) growth and its interaction with the extracellular matrix (ECM) to investigate the mechanical conditions that may lead to tumor microinvasions. SilicoDCIS simulates the division, growth, and migration of tumor cells in DCIS while interacting with other cell types and the ECM. This includes the BM, the myoepithelial and epithelial cell layers, and the collagen in the ECM. The ECM was modeled as a vector field, where the direction of each vector gives the orientation of a collagen bundle, and the vector magnitude is related to the bundle density. The growing DCIS can remodel the ECM (density and orientation), and in turn, the ECM applies a reciprocal force (proportional to the local collagen density) opposite to the tumor growth. With SilicoDCIS, we studied the mechanical effects of cancer cell proliferation and migration on the BM and the ECM. We found that higher cell migration force leads to increased BM stress and ECM density (on the tumor edges where cells migrate) and that the escape of the migrating cells from the duct vs. their intraductal confinement depends on cell speed. SilicoDCIS may provide insights into the mechanics of DCIS microinvasions to guide the design of future experiments.
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