Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia

Abstract

SUMMARY Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.

Screen for Slit/Robo signaling in trunk neural cells reveals new players

“…One of the best known roles of Robo signaling is its effect on the cells cytoskeleton (Blockus and Chedotal, 2016; McConnell et al, 2016; Vaughen and Igaki, 2016). Results from our microarray further supported the hypothesis that Slit/Robo signaling has a wider effect on neural crest cells cytoskeleton than previously thought.…”

“…Recent findings by Vaughen and Igaki in Drosophila further supports this hypothesis. They present data that demonstrates a role for Slit/Robo via E-cadherin (E-cad) deregulation in extruding tumorigenic cells from epithelia (Vaughen and Igaki, 2016). Their findings help to explain how Slit/Robo signaling acts both as tumor suppressor and/or promoter in variety of cancers, and how this can be applied to the process of NCC becoming migratory upon delamination.…”

“…Of especial relevance is the fact that pre-migratory neural crest cells (NCC) express Slits and Robo receptor simultaneously (Giovannone et al, 2012). While we know that trunk neural crest cells are repelled by Slit molecules (Giovannone et al, 2012; Vaughen and Igaki, 2016; Zuhdi et al, 2015), and that neural crest cells over-expressing Robo1-Δ-67 do not migrate along their ventromedial pathway (Jia et al, 2005), we still do not have a clear picture among the many possible downstream pathways of Robo, which ones are involved in these responses (Blockus and Chedotal, 2016). Are Slit molecules modulating the proliferation of neural crest cells?…”

Making Connections: Guidance Cues and Receptors at Nonneural Cell–Cell Junctions

“…In flies, Slit/Robo signaling inhibits the formation of cadherin-mediated cell-cell junctions during heart development (Santiago-Martinez et al 2008). An interesting recent study in Drosophila provides evidence that Slit/Robo repellent signaling through JNK extrudes tumorigenic cells from epithelia by disrupting E-cadherin function (Vaughen and Igaki 2016). The investigators found that overexpression of Slit/Robo2 results in cells being dislocated from the epithelial surface, resulting in tumor formation within the luminal space.…”

“…The investigators found that overexpression of Slit/Robo2 results in cells being dislocated from the epithelial surface, resulting in tumor formation within the luminal space. In contrast, loss of Slit/Robo2 signaling prevents cell extrusion, leading to tumor growth within the epithelium (Vaughen and Igaki 2016). In this way, the investigators propose that both over-and underactivation of Slit/Robo2 signaling contributes to tumorigenesis and cancer progression.…”