Gloria Slattum1, Yapeng Gu1, Roger Sabbadini2, Jody Rosenblatt3. 1. Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA. 2. Lpath, Inc., 4025 Sorrento Valley Boulevard, San Diego, CA 92121, USA. 3. Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA. Electronic address: jody.rosenblatt@hci.utah.edu.
Abstract
BACKGROUND: To maintain a protective barrier, epithelia extrude cells destined to die by contracting a band of actin and myosin. Although extrusion can remove cells triggered to die by apoptotic stimuli, to maintain constant cell numbers, epithelia extrude live cells, which later die by anoikis. Because transformed cells may override anoikis and survive after extrusion, the direction of extrusion has important consequences for the extruded cell's fate. As most cells extrude apically, they are typically eliminated through the lumen; however, cells with upregulated survival signals that extrude basally could potentially invade the underlying tissue and migrate to other sites in the body. RESULTS: We found that oncogenic K-Ras cells predominantly extrude basally, rather than apically, in a cell-autonomous manner and can survive and proliferate after extrusion. Expression of K-Ras(V12) downregulates the bioactive lipid sphingosine 1-phosphate (S1P) and its receptor S1P2, both of which are required for apical extrusion. Surprisingly, the S1P biosynthetic pathway is not affected because the S1P precursor, sphingosine kinase, and the degradative enzymes S1P lyase and S1PP phosphatase are not significantly altered. Instead, we found that high levels of autophagy in extruding Ras(V12) cells leads to S1P degradation. Disruption of autophagy chemically or genetically in K-Ras(V12) cells rescues S1P localization and apical extrusion. CONCLUSIONS: Oncogenic K-Ras cells downregulate both S1P and its receptor S1P2 to promote basal extrusion. Because live basally extruding cells can survive and proliferate after extrusion, we propose that basal cell extrusion provides a novel mechanism for cells to exit the epithelium and initiate invasion into the surrounding tissues.
BACKGROUND: To maintain a protective barrier, epithelia extrude cells destined to die by contracting a band of actin and myosin. Although extrusion can remove cells triggered to die by apoptotic stimuli, to maintain constant cell numbers, epithelia extrude live cells, which later die by anoikis. Because transformed cells may override anoikis and survive after extrusion, the direction of extrusion has important consequences for the extruded cell's fate. As most cells extrude apically, they are typically eliminated through the lumen; however, cells with upregulated survival signals that extrude basally could potentially invade the underlying tissue and migrate to other sites in the body. RESULTS: We found that oncogenic K-Ras cells predominantly extrude basally, rather than apically, in a cell-autonomous manner and can survive and proliferate after extrusion. Expression of K-Ras(V12) downregulates the bioactive lipidsphingosine 1-phosphate (S1P) and its receptor S1P2, both of which are required for apical extrusion. Surprisingly, the S1P biosynthetic pathway is not affected because the S1P precursor, sphingosine kinase, and the degradative enzymes S1P lyase and S1PP phosphatase are not significantly altered. Instead, we found that high levels of autophagy in extruding Ras(V12) cells leads to S1P degradation. Disruption of autophagy chemically or genetically in K-Ras(V12) cells rescues S1P localization and apical extrusion. CONCLUSIONS: Oncogenic K-Ras cells downregulate both S1P and its receptor S1P2 to promote basal extrusion. Because live basally extruding cells can survive and proliferate after extrusion, we propose that basal cell extrusion provides a novel mechanism for cells to exit the epithelium and initiate invasion into the surrounding tissues.
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