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Does Extrusion Drive Metastasis Initiation?

Because tumor cells often over-express signals that block cell death but still allow extrusion, extrusion could potentially suppress accumulation of tumors or initiate their metastasis, depending on the direction live cells are extruded. In collaboration with Bryan Welm's lab, we are investigating if extrusion could provide a previously unrecognized mechanism for tumor cells to initiate metastasis using wildtype and transformed mouse mammary organoids. Work from the Welm Lab has shown that mouse epithelial stem cells can be cultured in matrix to form a bilayered organoid (see A), which will develop into a mammary gland when transplanted back into cleared mammary fat pads. We find that inducing cell death triggers extrusion of dying cells into the lumen (apically) and out of the organoid (basally) (as in B). Inhibition of caspases with ZVAD blocks cell death but not extrusion (see C). Some of the extruded cells appear to migrate from the organoid, and we plan to test the ultimate fate of the extruded cells.