Linking Changes in Epithelial Morphogenesis to Cancer Mutations Using Computational Modeling

Katarzyna A. Rejniak, Shizhen E. Wang, Nicole S. Bryce, Hang Chang, Bahram Parvin, Jerome Jourquin, Lourdes Estrada, Joe W. Gray, Carlos L. Arteaga, Alissa M. Weaver, Vito Quaranta, Alexander R. A. Anderson

Abstract: Author Summary The majority of tumors arise in epithelial tissues that form monolayers of tightly packed cells enclosing the inner ductal or lobular cavities. Epithelial tumors (carcinomas) are associated with a disruption of epithelial architecture, such as filling of the inner lumen in the early stages of cancer, or the distortion of the ductal structure and spreading to the surrounding stroma in the subsequent invasive stages of tumor. Non-tumorigenic epithelial cells grown in 3D in vitro cultures form regular monolayered spheroids with hollow lumen (acini, Fig. 1a) resembling the architecture of normal epithelial cysts. In contrast, tumor cells taken from patients' biopsies and grown in 3D culture acquire various morphologies, often loosing the epithelial-like architecture. How these molecular defects produce such abnormal morphologies remains an open issue. We propose here to use the bio-mechanical model of epithelial morphogenesis, IBCell, to quantitatively investigate the phenotypical changes that the epithelial cells need to obtain in order to produce the aberrant morphologies observable experimentally and clinically. IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the link between histopathology of early tumors and underlying molecular defects.