Autophagy in Oncogenic K-Ras Promotes Basal Extrusion of Epithelial Cells by Degrading S1P

Current biology: CB (Impact Factor: 9.57). 12/2013; 24(1). DOI: 10.1016/j.cub.2013.11.029
Source: PubMed


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.
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.
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.

Download full-text


Available from: Jody Rosenblatt, Jan 21, 2014
1 Follower
37 Reads
  • Source
    • "Therefore, live-cell extrusion and subsequent apoptosis has been proposed to be a tumour-suppressive process that prevents the formation of multilayered epithelia (Eisenhoffer et al., 2012; Eisenhoffer and Rosenblatt, 2013). Events of live-cell extrusion have also been observed upon the activation of different oncogenes (such as K-Ras, H-Ras, Src and ERBB2) within single cells of an epithelium (Hogan et al., 2009; Kajita et al., 2010; Leung and Brugge, 2012; Slattum et al., 2014; Wu et al., 2014). These oncogene-driven extrusion events are subsequently coupled to proliferation, not apoptosis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epithelial cell extrusion and subsequent apoptosis is a key mechanism to prevent accumulation of excess cells. Conversely, when driven by oncogene expression, apical cell extrusion is followed by proliferation and represents an initial step of tumorigenesis. E-cadherin (E-cad), the main component of adherens junctions, has been shown to be essential for epithelial cell extrusion, but its mechanistic contribution remains unclear. Here, we provide clear evidence that cell extrusion can be driven by E-cad cleavage, both in a wild type and oncogenic environment. We first show that CDC42 activation in a single epithelial cell results in its efficient MMP-sensitive extrusion through MEK signaling activation and is supported by E-cad cleavage. Second, using an engineered cleavable form of E-cad, we demonstrate that sole extracellular E-cad truncation at the plasma membrane promotes apical extrusion. We propose that extracellular cleavage of E-cad generates a rapid change in cell-cell adhesion sufficient to drive apical cell extrusion. Whereas in normal epithelia, extrusion is followed by apoptosis, when combined to active oncogenic signaling, it is coupled to cell proliferation.
    Journal of Cell Science 06/2014; 127(15). DOI:10.1242/jcs.147926 · 5.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastasis is the leading cause of cancer-related deaths, but it is unclear how cancer cells escape their primary sites in epithelia and disseminate to other sites in the body. One emerging possibility is that transformed epithelial cells could invade the underlying tissue by a process called cell extrusion, which epithelia use to remove cells without disrupting their barrier function. Typically, during normal cell turnover, live cells extrude apically from the epithelium into the lumen and later die by anoikis; however, several oncogenic mutations shift cell extrusion basally, towards the tissue that the epithelium encases. Tumour cells with high levels of survival and motility signals could use basal extrusion to escape from the tissue and migrate to other sites within the body.
    Nature reviews. Cancer 06/2014; 14(7). DOI:10.1038/nrc3767 · 37.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RAS genes are frequently mutated in various human tumours. These mutations cause GTPase RAS to remain locked in constitutively active signals through the downstream cascades leading to proliferation. A series of earlier studies reported on the morphological appearance of cells upon RAS activation. Classically, morphologic changes of fibroblasts have been used to confirm the oncogenic activity of RAS. Recent works found that the active RAS induces benign and malignant morphological changes in organoids, which are an in vitro model system for epithelial tissue. The studies of animal models support the basic oncogenic features of RAS revealed in vitro, while also providing evidence that the effects of RAS activation in vivo are different from those in vitro. The pathological observation of the various human materials indicates that the oncogenic RAS participates in metaplasia, which occurs before proliferation, and that RAS promotes mucin production in various organs. These morphological analyses may shed light on important signalling pathways that merit investigation in vitro.
    Journal of Biochemistry 06/2014; 156(3). DOI:10.1093/jb/mvu041 · 2.58 Impact Factor
Show more