Morphological basis of the lung adenocarcinoma subtypes

Lung adenocarcinoma (LUAD), which accounts for a large proportion of lung cancers, is divided into five major subtypes based on histologic characteristics. The clinical characteristics, prognosis, and responses to treatments vary among subtypes. Here, we demonstrate that the variations of cell-cell contact energy result in the LUAD subtype-specific morphogenesis. We reproduced the morphologies of the papillary LUAD subtypes with the cellular Potts Model (CPM). Simulations and experimental validations revealed modifications of cell-cell contact energy changed the morphology from a papillary-like structure to micropapillary or solid subtype-like structures. Remarkably, differential gene expression analysis revealed subtype-specific expressions of genes relating to cell adhesion. Knockdown experiments of the micropapillary upregulated ITGA11 gene resulted in the morphological changes of the spheroids produced from an LUAD cell line PC9. This work shows the consequences of gene mutations and gene expressions on patient prognosis through differences in tissue composing physical forces among LUAD subtypes.