Multiscale modeling predicts dependence of mesenchymally transitioned tumor niche fitness on cell-cell and cell-matrix adhesions

Abstract Invasion of cancer cells is often characterized by a transition in phenotype of cells or their niches from an epithelial to a mesenchymal state (EMT). Under what conditions do transitioned niches acquire greater fitness than, and outcompete, their parental un-transitioned niches, is not well-understood. Here, we use a Cellular Potts model-based multiscale computational framework to investigate this question. Inducing an EMT in a single cell at the edge of an early-growing tumor surrounded by a fibrillar extracellular matrix (ECM) allows us to temporally trace inter-niche competitions. We observe that the transitioned niche dominates the population it arises from and invades better when surrounded by dense ECM. An increase in cell-ECM adhesion by itself drives domination at 50% probability, such that the transitioned population invades faster and contributes further to collective invasion of the whole tumor. Decrease in inter- and intra-niche cell-cell adhesion by itself is not sufficient to achieve domination. However, added to increased cell-ECM adhesion, loss of intra-niche (but not inter-niche adhesion) restores the probability, but not the extent, with which domination by the transitioned niche is achieved by attenuating its confinement by its parental population. Our simulations reveal the forces regulating such confinement and how cell-cell and cell-ECM adhesion, stochastic invasion dynamics, and ECM density contribute nuancedly to distinct aspects of inter-niche competitions within tumor populations and their fitness.