Browsing by Author "Brodland, Wayne"

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A biomechanical analysis of ventral furrow formation in the Drosophila melanogaster embryo
(Public Library of Science (PLOS), 2012) Conte, Vito; Ulrich, Florian; Baum, Buzz; Munoz, Jose; Veldhuis, Jim; Brodland, Wayne; Miodownik, Mark
The article provides a biomechanical analysis of ventral furrow formation in the Drosophila melanogaster embryo. Ventral furrow formation is the first large-scale morphogenetic movement in the fly embryo. It involves deformation of a uniform cellular monolayer formed following cellularisation, and has therefore long been used as a simple system in which to explore the role of mechanics in force generation. Here we use a quantitative framework to carry out a systematic perturbation analysis to determine the role of each of the active forces observed. The analysis confirms that ventral furrow invagination arises from a combination of apical constriction and apical-basal shortening forces in the mesoderm, together with a combination of ectodermal forces. We show that the mesodermal forces are crucial for invagination: the loss of apical constriction leads to a loss of the furrow, while the mesodermal radial shortening forces are the primary cause of the internalisation of the future mesoderm as the furrow rises. Ectodermal forces play a minor but significant role in furrow formation: without ectodermal forces the furrow is slower to form, does not close properly and has an aberrant morphology. Nevertheless, despite changes in the active mesodermal and ectodermal forces lead to changes in the timing and extent of furrow, invagination is eventually achieved in most cases, implying that the system is robust to perturbation and therefore over-determined.
The Biomechanics of Mammary Epithelial Morphogenesis
(University of Waterloo, 2017-04-28) Perrone, Matthew; Brodland, Wayne
Major organs and tissues such as the lung, kidney, liver, and the salivary and mammary glands are complex structures, but share a fundamental building block – epithelial cells. During tissue formation – a process known as morphogenesis – epithelial cells express motile behaviour. Although numerous identified transcripts, genes, and molecular pathways are responsible for the epithelial spatial organization of these organs; the way in which epithelial cells move and rearrange to form tissues is incompletely understood. Advanced imaging techniques provide snapshots of epithelial morphogenesis, but do not reveal cell motions or the forces that drive them. The goal of this study was to use biomechanics and computational modeling to fill this knowledge gap by identifying and confirming the cellular mechanics of mammary epithelial tube morphogenesis. Identifying these motile behaviours connects the transcripts, genes, and molecular pathways responsible for morphogenesis to the resulting cellular movements. In addition, many invasive carcinomas originate in epithelial tissues of major organs and it is the epithelial cells that become malignant. Knowledge of how carcinomas acquire motile behaviours is of particular interest in the field of medicine as it may lead to a better understanding of metastasis – a deadly disease responsible for approximately 90% of cancer-related deaths. Identifying the motile behaviours of epithelial cells during morphogenesis provides a mechanical basis of understanding how invasive carcinomas may move during the early stages of metastasis. In this study, inference techniques were applied to 3D images of in vitro cells in organoids to determine the interfacial tensions associated with the molecular activities and cellular behaviours proposed to drive epithelial tube morphogenesis. Then, finite element (FE) modeling was used to confirm the sufficiency of the identified interfacial tensions to drive epithelial tube morphogenesis. The model showed that various combinations of interfacial tensions are sufficient to drive cell migration and intercalation and, when combined with a time-varying boundary capture mechanism and high basal stress, are sufficient to drive tube elongation and polarization. Finally, a prediction model was proposed in which cell motility behaviour may be predicted solely by force inference from cell geometry. This study demonstrates that computational modeling can act as a novel window into a biological system by providing insights that cannot be obtained by advanced imaging and other means. This study also illustrates the importance of iterative dialogue between physical experimentation and modelling for developing a quantitative understanding of how cells collectively behave to form complex tissues and organs.
A Finite Element Investigation of Possible Mechanisms of Luminal Cell Escape from the Mammary Duct: An Initial Step in Breast Cancer Metastasis
(University of Waterloo, 2017-06-14) Kang, Jae; Brodland, Wayne
Cancer is an illness that kills some ten million people every year, and as cancer rates increase, a cure for metastatic disease is more necessary than ever. Breast cancer is the most common form of malignancy in the female population, with 1 in 8 women developing invasive ductal carcinoma (IDC) in their lifetime. The majority of cancer deaths are caused by metastasis, a process in which cancer cells spread throughout the body and invade multiple vital organs as a result of increased motility. Cell biomechanics is a nascent field in oncology, and it investigates cell movement and rearrangement in terms of mechanical forces and deformations. The Differential Interfacial Tension Hypothesis (DITH) provides a way to calculate the net tensions that subcellular components generate along cell boundaries and that give rise to deformation and rearrangement of individual cells and groups of cells. Finite element (FE) software can be used to model these forces and their interactions with each other. To date, this approach has made it possible to study a wide range of morphological phenomena, including wound healing, organ development and metastatic cell migration. The goal of this study was to use this software to investigate the escape of a single luminal epithelial (LE) cell from a mammary duct – the first stage of breast cancer metastasis. Mechanisms that were considered include: modified interfacial tensions (MIT), protrusions (P) and tension gradients (TG). The simulations showed that escape of a metastatic LE cell involves two consecutive stages – detachment from the mammary duct and migration through the extracellular matrix. The simulations showed that MIT alone can produce LE cell detachment, while protrusions alone or tension gradients alone can produce migration of cells through the ECM; Mechanisms can act in concert to speed escape and migration, and no single mechanism is able to produce both escape and migration. The simulations reflect behaviours seen in experiments in organoids and other in vitro systems, adding support for the simulation findings. Hopefully, the insights provided by this study will help lead to better understanding of the mechanics of cancer cell escape and migration, and to improved strategies for metastasis prevention.