Epithelial dynamics are critical during embryonic development and wound healing and are hijacked by cancer cells during the process of metastasis. We have developed a genetically tractable in vivo model to study a group of epithelial cells, the border cells of the Drosophila ovary, which exhibit dynamic cell behaviors including acquiring motility, detaching from an epithelium, migrating through neighboring tissue, and adhering to new cells at a distant site. While most studies of cell movements have focused on individual cells in vitro, cells frequently move in groups in vivo. Recently it has become clear that dissemination of clusters of cells is a common source of metastases in cancer. Most studies of both individual and collective cell motility focus on the intermediate step as cells migrate from one place to another. Little is known of the mechanisms by which cell collectives break away from their initial neighbors in the process of delamination. Even less is known about how cells make new connections upon arrival at their ultimate destination. To be concise we name this process neolamination. Here we propose to use the border cells to study the mysterious process of neolamination: attaching to a new site. In our first aim we build on a strong foundation of preliminary data describing the process by which border cells, after detaching from one epithelium and migrating for several hours, connect up to two new cell types: the oocyte and centripetal follicle cells. We report the identification of genes required for the process, providing the first clues to the molecular mechanism.
In Aim 1, we propose to combine opto- and thermo-genetic approaches that have revolutionized neuroscience and state-of-the-art methods for imaging direct protein- protein interactions in living tissue, to study this essential, yet essentially unstudied, process.
In Aim 2, we propose to study the cell biological processes and molecular mechanisms operating within the oocyte during the neolamination process.
In Aim 3, we propose to use the same set of highly innovative approaches to study how border cells initially leave their epithelium of origin, in the process of delamination. Having described the delamination process at unprecedented resolution, we propose to study the underlying cellular and molecular mechanisms. The overarching goal is to build a conceptual model describing how the border cells integrate multiple extracellular signals to execute collective delamination and neolamination and establish a paradigm for the study of these critical dynamic cellular behaviors.
Metastasis, the process by which tumor cells spread through the body, remains the major challenge in the clinical management of cancer. The first step in metastasis is that tumor cells detach from the original tumor and the last step is reattachment of the cells to a new site. Similar phenomena occur during normal tissue development, and here we propose to use a powerful experimental model we have developed to study the cellular and molecular mechanisms that drive these critical cellular behaviors.
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