Yorkie and JNK Control Tumorigenesis in Drosophila Cells with Cytokinesis Failure

Abstract

Cytokinesis failure may result in the formation of polyploid cells, and subsequent mitosis can lead to aneuploidy and tumor formation. Tumor suppressor mechanisms limiting the oncogenic potential of these cells have been described. However, the universal applicability of these tumor-suppressive barriers remains controversial. Here, we use Drosophila epithelial cells to investigate the consequences of cytokinesis failure in vivo. We report that cleavage defects trigger the activation of the JNK pathway, leading to downregulation of the inhibitor of apoptosis DIAP1 and programmed cell death. Yorkie overcomes the tumor-suppressive role of JNK and induces neoplasia. Yorkie regulates the cell cycle phosphatase Cdc25/string, which drives tumorigenesis in a context of cytokinesis failure. These results highlight the functional significance of the JNK pathway in epithelial cells with defective cytokinesis and elucidate a mechanism used by emerging tumor cells to bypass this tumor-suppressive barrier and develop into tumors.

Cell Cycle Asynchrony Generates DNA Damage at Mitotic Entry in Polyploid Cells

“…Not all Drosophila proliferative tissues were tolerant to polyploidy. Analysis of mutant wing discs, revealed severe development and proliferative defects accompanied by the presence of pyknotic nuclei, consistent with cell death reported in this tissue after cytokinesis inhibition [15] (Supplementary Figure 1B and data not shown).…”

Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model

“…There is clearly complex interplay between the pathways, highly dependent on cellular context, but its elucidation is critical for obtaining a more complete understanding of pro-and anti-tumourigenic JNK signalling. While recent research discussed in this review has undoubtedly advanced our knowledge greatly (Doggett et al, 2011;Sun and Irvine, 2011;Chen et al, 2012;Enomoto et al, 2015;Ma et al, 2015aMa et al, , 2017Gerlach et al, 2018), there is still much to be discovered, particularly with regard to how the pathways interact during cooperative tumourigenesis. This relationship between JNK and SWH signalling is undoubtedly one that will be examined closely in coming years.…”

“…Interactions between JNK signalling and SWH/Yki in the context of JNK acting in an anti-tumourigenic role are not limited to the context of disrupted cell polarity. Inducing cytokinesis failure in wing imaginal disc cells promotes aneuploidy, which can lead to tumourigenesis, but JNK signalling is also upregulated in these cells and acts to downregulate Diap1 and a cell cycle regulator, String (Stg, orthologue of the human CDC25 proteins), thus promoting cell death and suppressing cell proliferation (Gerlach et al, 2018). However, SWH inhibition or Yki activation can bypass this JNK-mediated tumourigenesis prevention by facilitating Diap1 and Stg upregulation (Gerlach et al, 2018).…”

Genome-wide RNAi screen for context-dependent tumor suppressors identified using in vivo models for neoplasia in Drosophila

“…Indeed, YAP overexpression has been causally linked to formation of specific human tumors [43,44]. The Hippo pathway has also been implicated in tumor formation resulting from cytokinesis failure [45] and this has recently been linked to Yki-mediated regulation of string (CDC25) expression [46]. The sensitivity of Ykiexpressing tissue to tumor formation might be explained by the finding that Yki promotes cell cycle progression at both the G1-S transition (through regulation of cycE [7] and at the G2-M transition through regulation of string.…”