A 3D Computational Study on the Formation and Progression of Tumor Cells in Diffuse Gastric Cancer.

Hereditary diffuse gastric cancer is characterized by an increased risk of diffuse gastric cancer and lobular breast cancer, and is caused by pathogenic germline variants of E-cadherin and -E-catenin, which are key regulators of cell-cell adhesion. However, how the loss of cell-cell adhesion promotes cell dissemination remains to be fully understood. Therefore, a three-dimensional computer model was developed to describe the initial steps of diffuse gastric cancer development. In this model, we have implemented a cellular Potts approach that contemplates cell adhesion to other cells and to the extracellular matrix, cell extrusion from the gastric epithelia, and subsequent proliferation. We demonstrate that early disease features are determined by decreased adhesion of mutant cells to their normal epithelial neighbors, with concomitant increased attachment to matrix components. Importantly, our simulation shows how mechanical pressure and uncontrolled proliferation of mutant cells lead to modifications in cell shape and in gastric gland morphology. In conclusion, this work underscores the potential of computational models to elucidate the role of cellular and noncellular components in gastric cancer that may be relevant targets in therapeutic interventions.