Collective cell migration in a fibrous environment:a hybrid multi-scale modelling approach

International audienceThe specific structure of the extracellular matrix (ECM), and in particular the density and orientation of collagen fibres, plays an important role in the evolution of solid cancers. While many experimental studies discussed the role of ECM in individual and collective cell migration, there are still unanswered questions about the impact of nonlocal cell sensing of other cells on the overall shape of tumour aggregation and its migration type. There are also unanswered questions about the migration and spread of tumour that arises at the boundary between different tissues with different collagen fibre orientations. To address these questions, in this study we develop a hybrid multi-scale model that considers the cells as individual entities and ECM as a continuous field. The numerical simulations obtained through this model match experimental observations, confirming that tumour aggregations are not moving if the ECM fibres are distributed randomly, and they only move when the ECM fibres are highly aligned. Moreover, the stationary tumour aggregations can have circular shapes or irregular shapes (with finger-like protrusions), while the moving tumour aggregations have elongate shapes (resembling to clusters, strands or files). We also show that the cell sensing radius impacts tumour shape only when there is a low ratio of fibre to non-fibre ECM components. Finally, we investigate the impact of different ECM fibre orientations corresponding to different tissues, on the overall tumour invasion of these neighbouring tissues

Linking Changes in Epithelial Morphogenesis to Cancer Mutations Using Computational Modeling

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

Homeostatic Imbalance in Epithelial Ducts and Its Role in Carcinogenesis

An epithelial duct is a well-defined multicellular structure composed of tightly packed cells separating and protecting body compartments that are used for enzyme secretion and its transport across the internal. The structural and functional integrity (homeostasis) of such ducts is vital in carrying many life functions (breathing, lactation, production of hormones). However, the processes involved in maintaining the homeostatic balance are not yet fully understood. On the other hand, the loss of epithelial tissue architecture, such as filled lumens or ductal disorganization, are among the first symptoms of the emerging epithelial tumors (carcinomas). Using the previously developed biomechanical model of epithelial ducts: IBCell, we investigated how different signals and mechanical stimuli imposed on individual epithelial cells can impact the homeostatic (im)balance and integrity of the whole epithelial tissue. We provide a link between erroneous responses of individual epithelial cells to specific signals and the emerging ductal morphologies characteristic for preinvasive cancers observed in pathology specimens, or characteristic for multicellular structures arising from mutated cells cultured in vitro. We summarize our finding in terms of altered properties of epithelial cell polarization, and discuss the relative importance of various polarization signals on the formation of tumor-like multicellular structures

Homeostatic Imbalance in Epithelial Ducts and Its Role in Carcinogenesis

An epithelial duct is a well-defined multicellular structure composed of tightly packed cells separating and protecting body compartments that are used for enzyme secretion and its transport across the internal. The structural and functional integrity (homeostasis) of such ducts is vital in carrying many life functions (breathing, lactation, production of hormones). However, the processes involved in maintaining the homeostatic balance are not yet fully understood. On the other hand, the loss of epithelial tissue architecture, such as filled lumens or ductal disorganization, are among the first symptoms of the emerging epithelial tumors (carcinomas). Using the previously developed biomechanical model of epithelial ducts: IBCell, we investigated how different signals and mechanical stimuli imposed on individual epithelial cells can impact the homeostatic (im)balance and integrity of the whole epithelial tissue. We provide a link between erroneous responses of individual epithelial cells to specific signals and the emerging ductal morphologies characteristic for preinvasive cancers observed in pathology specimens, or characteristic for multicellular structures arising from mutated cells cultured in vitro. We summarize our finding in terms of altered properties of epithelial cell polarization, and discuss the relative importance of various polarization signals on the formation of tumor-like multicellular structures

Homeostatic Imbalance in Epithelial Ducts and Its Role in Carcinogenesis

An epithelial duct is a well-defined multicellular structure composed of tightly packed cells separating and protecting body compartments that are used for enzyme secretion and its transport across the internal. The structural and functional integrity (homeostasis) of such ducts is vital in carrying many life functions (breathing, lactation, production of hormones). However, the processes involved in maintaining the homeostatic balance are not yet fully understood. On the other hand, the loss of epithelial tissue architecture, such as filled lumens or ductal disorganization, are among the first symptoms of the emerging epithelial tumors (carcinomas). Using the previously developed biomechanical model of epithelial ducts: IBCell, we investigated how different signals and mechanical stimuli imposed on individual epithelial cells can impact the homeostatic (im)balance and integrity of the whole epithelial tissue. We provide a link between erroneous responses of individual epithelial cells to specific signals and the emerging ductal morphologies characteristic for preinvasive cancers observed in pathology specimens, or characteristic for multicellular structures arising from mutated cells cultured in vitro. We summarize our finding in terms of altered properties of epithelial cell polarization, and discuss the relative importance of various polarization signals on the formation of tumor-like multicellular structures