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.
Highlights
The environment in which tumor cells are growing in vivo can be very complex, and may include distinct stromal cells, normal or aberrant vasculature, inhomogeneous concentrations of nutrients, proteases or growth factors, gradients in interstitial pressure or non-uniform alignment and cross-linking of various fibrous proteins forming the extracellular matrix (ECM)
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
In this paper we presented an integrative approach combining in vitro experiments, confocal image analysis and quantification, and high throughput simulation studies to understand the relationship between phenotypic and molecular changes in certain mutated cells when compared with their parental non-tumorigenic cell line
Summary
The environment in which tumor cells are growing in vivo can be very complex, and may include distinct stromal cells, normal or aberrant vasculature, inhomogeneous concentrations of nutrients, proteases or growth factors, gradients in interstitial pressure or non-uniform alignment and cross-linking of various fibrous proteins forming the extracellular matrix (ECM). Since the cells are exposed to these various and often contradictory microenvironmental cues, and they can actively participate in remodeling of the physical structure and chemical composition of the stroma, it is difficult to predict tumor progression and response to treatments. The change in cell phenotypic state (i.e., the initiation of cell proliferation or death, cell epithelial polarization or epithelial-mesenchymal transition) depends on cell intrinsic sensitivity to extrinsic cues from the surrounding microenvironment, and on cell robustness and adaptability to microenvironmental conditions. Several in vivo techniques have been used to investigate interactions between individual cells and to test cell responses to various extrinsic cues in more controlled conditions. One would like to be able to make an initial assessment about the possible molecular changes or underlying mutations by examining the morphology of the multicellular structures grown from mutated or tumorigenic cells
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