Dynamic Organization of Cell Architecture in Multicellular Tissues

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PROJECT SUMMARY: Dynamic Organization of Cell Architecture in Multicellular Tissues The majority of human cancers are derived from epithelial tissues. In carcinomas, advancement to metastasis, which is characteristic of the terminal stages of tumor progression, accounts for over 90% of mortality. The events that lead to tumor cell metastasis have been investigated through studies of tumor cell behavior, which suggest that tumor invasion can initiate through collective cell migration. Collectively migrating tumor cells share many similarities with single cell migration and with dynamically remodeling epithelial tissues during development. However, while the signaling mechanisms underlying single cell migration have been extensively studied, the mechanisms that coordinate cell behaviors in dynamically remodeling multicellular tissues are less well understood. Tissue remodeling in epithelia requires the organization of cell polarity and behavior in the plane of the tissue, a property referred to as planar polarity. The early Drosophila embryo is a simple multicellular epithelium in which the planar polarized localization of proteins involved in contraction and adhesion cause the tissue to undergo dramatic changes in shape to produce an elongated head-to-tail body axis. The goal of this project is to dissect the signaling mechanisms involved in establishing planar polarity and regulating planar polarized cell rearrangements in this dynamically remodeling tissue. Specifically, these studies will determine the molecular pathways that translate interactions between neighboring cells into spatially regulated changes in the organization of the actin cytoskeleton. In Aim 1, I will perform loss and gain of function studies in order to identify key signaling pathways involved in regulating the planar polarized localization of proteins involved in junctional remodeling during axis elongation, with a focus on proteins that regulate the organization and dynamics of the actomyosin cytoskeleton. In Aim 2, I will study how these processes are regulated by extracellular cues provided by local interactions between cells to orient and coordinate actin reorganization across a multicellular population. These studies will reveal how external signals are translated into planar polarized changes in cell behavior during epithelial development and will provide insight into the fundamental mechanisms that control the spatially regulated organization and remodeling of the actin cytoskeleton in a multicellular tissue. Insight into the regulation of cell behavior and actomyosin dynamics in vivo can help to elucidate the mechanisms that control collective cell behavior in other contexts, such as during the invasion and metastasis of epithelial tumors.