Elimination of oncogenic cells that regulate epithelial homeostasis in Drosophila

Abstract

Normal epithelial tissues often put anti-tumorigenic pressure on newly emerged oncogenic cells through cell-cell communications. In Drosophila epithelium, clones of oncogenic cells mutant for evolutionarily conserved apico-basal polarity genes such as scribble (scrib) and discs large (dlg) are actively eliminated when surrounded by normal cells. It has been reported that c-Jun N-terminal kinase (JNK) signaling in polarity-deficient cells is crucial for their cell death. However, the mechanism by which normal epithelial tissues exert anti-tumorigenic effects on polarity-deficient cells had been elusive. Here, I describe our genetic studies in Drosophila epithelium especially focused on the role of surrounding normal epithelial cells in response to the emergence of polarity-deficient cells. Furthermore, I also describe recent studies regarding the mechanism by which polarity-deficient cells are extruded from the tissue, and discuss future perspectives on the study of cell-cell communications in epithelial homeostasis.

Keywords: Drosophila; cell-cell communication; oncogenic polarity-deficient cells; tumor suppressive cell competition.

Figure 1

Epithelial cells promote elimination of polarity‐deficient cells through Jun N‐terminal kinase (JNK)‐mediated Engulfment. In response to the emergence of oncogenic polarity‐deficient cells, surrounding wild‐type cells activate JNK signaling, which activates PVR‐ELMO/Mbc engulfment pathway. See text for details

Figure 2

Sas‐PTP10D drives elimination of polarity‐deficient cells. (a) Jun N‐terminal kinase (JNK) signaling induces elimination of polarity‐deficient cells by SAS/PTP10D‐mediated inhibition of EGFR signaling. (b) In the absence of SAS/PTP10D system, EGFR signaling switches JNK signaling from cell death to overgrowth. See text for details

Figure 3

Serpin5 is required for elimination of polarity‐deficient cells. (a) Secreted Serpin5 from epithelial cells facilitates elimination of polarity‐deficient cells by inhibiting activation of Toll signaling in polarity‐deficient cells. (b) In the absence of Serpin5, extracellular Spz activates Toll signaling in polarity‐deficient cells, which results in their overgrowth. See text for details

Figure 4

Jun N‐terminal kinase (JNK) signaling extrudes polarity‐deficient cells through autocrine Slit‐Robo2 repulsive system. In polarity‐deficient cells surrounded by wild‐type cells, JNK activates Slit‐Robo2‐Ena signaling leading to downregulation of E‐cadherin (a). In this normal situation, polarity‐deficient cells are predominantly basally extruded and cause apoptotic cell death (c). In the absence of Slit‐Robo2‐Ena signaling, polarity‐deficient cells escape from extrusion, leading to their overgrowth in the epithelial layers (b). Conversely, hyperactivation of Robo2‐Ena signaling induces excess extrusion and luminal tumors (d). See text for details