Identification of signals that extrude an apoptotic cell from an epithelium

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I have discovered a mechanism called `extrusion', by which dying cells exit the epithelium without disrupting the barrier function of the layer. Here, a cell destined to die, signals its surrounding neighboring cells to form an intercellular actomyosin ring that contracts to squeeze the dying cell out. While stimuli that induce cell death (apoptosis) activate extrusion, we have also found that apoptosis and extrusion are not interdependent. This suggests that extrusion may remove cells from the epithelium in other circumstances. Signals that promote extrusion could, therefore, be used when cells leave the epithelium during developmental differentiation or initiation of tumor cell metastasis. Because most high-grade tumors have mutations in the apoptotic pathway, mutations that block apoptosis but not extrusion could enable a tumor cell to easily exit the epithelium and initiate its metastasis to other sites. Because metastasis is generally associated with cancer lethality, we believe that understanding the signalling that drives extrusion may be of utmost importance. We will also explore if extrusion might precede and induce apoptosis in overcrowded regions during normal homeostasis as a way of regulating cell numbers. Identifying the signals that trigger extrusion will be key to understanding the physiological functions that extrusion plays. We plan to identify the signalling pathway that initiates commitment of cell extrusion by investigating where this pathway bifurcates from the apoptotic pathway. We will also identify the downstream extra-cellular lipid signal that elicits extruding ring formation, as we think that this signal might provide a good molecular marker for extrusion. With these signals in hand, we will be able to test the function of extrusion in potential processes ranging from maintaining epithelial numbers and function to novel mechanisms for tumor formation and initiating tumor cell metastasis. To do so, we will extend our extrusion studies into whole zebrafish embryos.