Speaker
Description
Microinvasions in ductal carcinoma in situ (DCIS) of breast cancer arise when malignant cells breach the basement membrane (BM) and invade the stroma. Since this is an early step in metastasis, identifying drivers of microinvasion may improve risk prediction and support treatment de-escalation. Mechanical tumor–stroma interactions, including extracellular matrix (ECM) collagen stiffening and deposition, are key contributors to the emergence of microinvasions, as is tumor acidity.
We developed silicoDCIS, an off-lattice agent-based model of a DCIS cross-section that incorporates tumor growth, ECM fibril bundle properties, and acidic microenvironmental effects to study conditions leading to microinvasions. The model simulates tumor cell division, migration, and lactate secretion, and captures interactions between epithelial cells, BM, myoepithelium, fibroblasts, and collagen.
The silicoDCIS model was parameterized to match the time points of DCIS development in HER2+ mouse experiments. We performed studies assessing mechanical contributions of DCIS components and the stroma to the emergence of microinvasion and how the proliferation-driven invasions can be prevented. We also integrated histology images to simulate spatial mechanical and metabolic interactions under acid stress to test whether acidosis-driven fibroblast reprogramming promotes stromal activation, ECM remodeling, and DCIS progression. This model can be used to generate new hypotheses of microinvasion development.
