Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia

Publication date: 19 December 2016
Source:Developmental Cell, Volume 39, Issue 6
Author(s): John Vaughen, Tatsushi Igaki
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.

Graphical abstract

Teaser

Tumor-suppressive programs remove aberrant cells from developing tissues. Vaughen and Igaki identify Slit-Robo2-Ena as the extrusive force behind polarity-deficient cell elimination from Drosophila epithelia. While loss of Slit-Robo2-Ena permits tumor formation within the epithelium, Slit-Robo2-Ena signaling hyperactivation triggers excess extrusion and luminal tumor overgrowth.


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