Linking Changes in Epithelial Morphogenesis to Cancer Mutations Using Computational Modeling

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Abstract
Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects. 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.