Constitutively activated AKT is not sufficient to keep cells alive following epithelial cell extrusion

honors thesisCollege of ScienceBiologyJody RosenblattThe PI3 kinase (PI3K)/AKT signaling pathway regulates many fundamental behaviors of the cell. If any of the key members of this pathway are deregulated, it can lead to malignant changes in the cell. AKT enhances the survival of cells by inhibiting pro-apoptotic processes, and promoting pathways for cell survival, important for cancer metastasis. Most solid tumors arise from the epithelium therefore I will address how differences in expression of pro-survival signals may affect epithelial tumors, or carcinomas. Our lab has found that to maintain constant cell numbers during epithelial homeostasis, excess cells are removed by extruding live cells that later die. Should misregulated PI3K/AKT cause cells to survive after extrusion, extrusion could enable cells to metastasize instead of eliminating excess cells, depending on the direction they extrude. If cells extrude the normal apical direction, then cells with upregulated survival signaling will still be eliminated through dead space. However, if cells extrude basal ly, they could access the underlying mesenchyme and initiate metastasis. Other oncogenic mutations have switched the direction of extrusion from predominantly apical to predominantly basal, therefore, we wondered if activation of AKT1 could also shift the direction of extrusion from apical to basal. I will test whether or not cancerous cells and non-cancerous cells over expressing AK.T1 can survive after they are extruded, and how downstream targets of the AKT1 pathway, like XlAP, affect directionality of extrusion and cell survival. This projcct is important for determining if common chemotherapies used on tumors over expressing AKT1 trigger invasion instead of ablation. However, I found that overexpression of AKT1 had no impact on the direction of extrusion or the ability of a cell to survive following extrusion