Aneuploidy-induced delaminating cells drive tumorigenesis in
            <i>Drosophila</i>
            epithelia

Dekanty, Andrés; Barrio, Lara; Muzzopappa, Mariana; Auer, Herbert; Milán, Marco

doi:10.1073/pnas.1206675109

Cited by 110 publications

(186 citation statements)

References 34 publications

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“…The activation of JNK subsequently eliminates these cells by activating the apoptotic programme. On the other hand, it has been recently reported that aneuploidy induces a Dp53-independent apoptosis that requires JNK (Dekanty et al, 2012). However, the initial apoptosis that we observed to be caused by the depletion of Dmp52 was partially dependent on JNK, as in the absence of JNK, apoptotic bodies could still be detected in the wing discs.…”

Section: Dp53 Physically Interacts With the Dmp52 Subunit Of Tfiihcontrasting

confidence: 42%

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

Villicaña¹,

Cruz²,

Zurita³

2013

Journal of Cell Science

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SummaryTranscription factor IIH (TFIIH) participates in transcription, nucleotide excision repair and the control of the cell cycle. In the present study, we demonstrate that the Dmp52 subunit of TFIIH in Drosophila physically interacts with the fly p53 homologue, Dp53. The depletion of Dmp52 in the wing disc generates chromosome fragility, increases apoptosis and produces wings with a reduced number of cells; cellular proliferation, however, is not affected. Interestingly, instead of suppressing the apoptotic phenotype, the depletion of Dp53 in Dmp52-depleted wing disc cells increases apoptosis and the number of cells that suffer from chromosome fragility. The apoptosis induced by the depletion of Dmp52 alone is partially dependent on the JNK pathway. In contrast, the enhanced apoptosis caused by the simultaneous depletion of Dp53 and Dmp52 is absolutely JNK-dependent. In this study, we also show that the anti-proliferative drug triptolide, which inhibits the ATPase activity of the XPB subunit of TFIIH, phenocopies the JNK-dependent massive apoptotic phenotype of Dp53-depleted wing disc cells; this observation suggests that the mechanism by which triptolide induces apoptosis in p53-deficient cancer cells involves the activation of the JNK death pathway.

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Section: Dp53 Physically Interacts With the Dmp52 Subunit Of Tfiihcontrasting

confidence: 42%

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

Villicaña¹,

Cruz²,

Zurita³

2013

Journal of Cell Science

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“…Consistent with an important role for centrosomes in fidelity, segregation errors significantly increased; 11.3% of anaphase cells had lagging chromosomes, bridges, or disorganized chromosomes versus 2.4% in WT (Fig.2K;p=0.022). Chromosome segregation defects can lead to aneuploidy, which initiates apoptosis in some cells (Dekanty et al, 2012; Sir et al, 2013). Thus, the increased apoptosis in acentrosomal wing cells could result from aneuploidy, although acentrosomal fly neuroblasts (neural progenitors; NBs) did not have a significant increase in aneuploidy (Basto et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Acentrosomal Drosophila Epithelial Cells Exhibit Abnormal Cell Division, Leading to Cell Death and Compensatory Proliferation

2014

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Summary Mitotic spindles are critical for accurate chromosome segregation. Centrosomes, the primary microtubule nucleating centers of animal cells, play key roles in forming and orienting mitotic spindles. However, the survival of Drosophila without centrosomes suggested they are dispensable in somatic cells, challenging the canonical view. We used fly wing disc epithelia as a model to resolve these conflicting hypotheses, revealing that centrosomes play vital roles in spindle assembly, function, and orientation. Many acentrosomal cells exhibit prolonged spindle assembly, chromosome mis-segregation, DNA damage, misoriented divisions, and eventual apoptosis. We found that multiple mechanisms buffer the effects of centrosome loss, including alternative microtubule nucleation pathways and the Spindle Assembly Checkpoint. Apoptosis of acentrosomal cells is mediated by JNK signaling, which also drives compensatory proliferation to maintain tissue integrity and viability. These data reveal the importance of centrosomes in fly epithelia, but also demonstrate the robust compensatory mechanisms at the cellular and organismal level.

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“…S1G). In these respects, extrusion of distal lgl − clones seen here is distinct from mutant clones displaying genomic instability, which often delaminate and turn neoplastic when rescued from cell death by a gain of p35 (23).…”

Section: Lgl − Somatic Clones Of Proximal and Distal Wing Primordia Dmentioning

confidence: 95%

Epithelial neoplasia in Drosophila entails switch to primitive cell states

Khan

Bajpai

Alam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Only select cell types in an organ display neoplasia when targeted oncogenically. How developmental lineage hierarchies of these cells prefigure their neoplastic propensities is not yet well-understood. Here we show that neoplastic Drosophila epithelial cells reverse their developmental commitments and switch to primitive cell states. In a context of alleviated tissue surveillance, for example, loss of Lethal giant larvae (Lgl) tumor suppressor in the wing primordium induced epithelial neoplasia in its Homothorax (Hth)-expressing proximal domain. Transcriptional profile of proximally transformed mosaic wing epithelium and functional tests revealed tumor cooperation by multiple signaling pathways. In contrast, lgl − clones in the Vestigial (Vg)-expressing distal wing epithelium were eliminated by cell death. Distal lgl − clones, however, could transform when both tissue surveillance and cell death were compromised genetically and, alternatively, when the transcription cofactor of Hippo signaling pathway, Yorkie (Yki), was activated, or when Ras/EGFR signaling was up-regulated. Furthermore, transforming distal lgl − clones displayed loss of Vg, suggesting reversal of their terminal cell fate commitment. In contrast, reinforcing a distal (wing) cell fate commitment in lgl − clones by gaining Vg arrested their neoplasia and induced cell death. We also show that neoplasia in both distal and proximal lgl − clones could progress in the absence of Hth, revealing Hth-independent wing epithelial neoplasia. Likewise, neoplasia in the eye primordium resulted in loss of Elav, a retinal cell marker; these, however, switched to an Hth-dependent primitive cell state. These results suggest a general characteristic of "cells-of-origin" in epithelial cancers, namely their propensity for switch to primitive cell states.

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Aneuploidy-induced delaminating cells drive tumorigenesis in Drosophila epithelia

Cited by 110 publications

References 34 publications

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

Acentrosomal Drosophila Epithelial Cells Exhibit Abnormal Cell Division, Leading to Cell Death and Compensatory Proliferation

Epithelial neoplasia in Drosophila entails switch to primitive cell states

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