Lopes Valéria, Figueiredo Joana, Carneiro Patrícia, Gouveia Marcos, Travasso Rui D M, Carvalho João
CFisUC, Department of Physics, University of Coimbra, Rua Larga, 3004-516, Coimbra, Portugal.
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Bull Math Biol. 2025 Jan 5;87(2):28. doi: 10.1007/s11538-024-01405-x.
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.
遗传性弥漫性胃癌的特征是弥漫性胃癌和小叶性乳腺癌的发病风险增加，它由E-钙黏蛋白和β-连环蛋白的致病性种系变异引起，而这两种蛋白是细胞间黏附的关键调节因子。然而，细胞间黏附丧失如何促进细胞播散仍有待充分了解。因此，我们开发了一个三维计算机模型来描述弥漫性胃癌发展的初始步骤。在这个模型中，我们采用了一种细胞Potts方法，该方法考虑了细胞与其他细胞以及细胞外基质的黏附、细胞从胃上皮的挤出以及随后的增殖。我们证明，早期疾病特征是由突变细胞与其正常上皮邻居的黏附减少以及与基质成分的附着增加所决定的。重要的是，我们的模拟显示了突变细胞的机械压力和不受控制的增殖如何导致细胞形状和胃腺形态的改变。总之，这项工作强调了计算模型在阐明胃癌中细胞和非细胞成分作用方面的潜力，这些成分可能是治疗干预的相关靶点。
