Tumor suppression by cell competition through regulation of the Hippo pathway

Chen, Chiao-Lin; Schroeder, Molly C.; Kango‐Singh, Madhuri; Tao, Chunyao; Halder, Georg

doi:10.1073/pnas.1113882109

Cited by 170 publications

(266 citation statements)

References 33 publications

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“…S1B), and also those of other Drosophila neoplastic tumor suppressors, are eliminated from mosaic imaginal disc epithelium by cell competition. Therefore, alleviation of cell competition in lgl − clones (and other neoplastic mutants) in a Minute (M − /M + ) surrounding is permissive for their survival and eventual neoplasia (15)(16)(17)(18) through successive days of their clonal growth (Fig. S1C).…”

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

confidence: 99%

“…7C), and were neoplastically transformed (actin) (Fig. 7C) (16,25,46). Importantly, scrib − M + eye clones (in an M − /M + surrounding) displayed an early gain of the retinal progenitor cell marker, Hth (day 3, Fig.…”

Section: -S)mentioning

confidence: 99%

“…9), its target dMyc (54), and its partner Hth (12), are thus likely to be crucial members of this core gene-set. It has been previously shown that Yki is activated upon loss of Lgl (46,55) or Scrib (16,31) while its target dMyc is a driver of neoplasia in lgl − (17) and scrib − (16) mutant cells. Further, mammalian homolog of Yki, namely, transcriptional co-activator with PDZ-binding motif (TAZ), induces stem cell-like characteristic in breast epithelial cells transformed by loss of the Scrib (56).…”

Section: -S)mentioning

confidence: 99%

“…13 and 14) mechanisms (subsequently referred to as tissue surveillance) has been suggested to restrain run away tumor growth in mammalian models. In Drosophila imaginal epithelia as well, tissue surveillance mechanisms, such as cell competition (15)(16)(17)(18) and intrinsic tumor suppression (19), have been implicated in elimination of neoplastic mutant clones.…”

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confidence: 99%

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

confidence: 99%

Section: -S)mentioning

confidence: 99%

Section: -S)mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Hence, cells lacking Hippo, or cells overexpressing Yorkie, overgrow [41][42][43] . Importantly, these overgrowing cells trigger apoptosi s in surrounding wild-type cells, a telltale sign of cell competition [44][45][46][47] . Like 3xMyc cells, Yorkie-overexpressing cells act as super-competitors, but there is at least one key difference.…”

Section: Apical-basal Determinantsmentioning

confidence: 99%

Mechanisms and mechanics of cell competition in epithelia

Vincent

Fletcher²,

Baena‐López

2013

Nat Rev Mol Cell Biol

123

121

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Modelling Cancer in Drosophila : The Next Generation

Cheng

Parsons

Richardson

2013

Encyclopedia of Life Sciences

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Drosophila melanogaster , the vinegar fly, has been utilised as a genetic amenable model organism for more than 100 years. In recent years, its use in modelling human cancer has been greatly expanding. In this article, an update of the recent advances in Drosophila research towards understanding cancer development is provided. Genetic analysis in Drosophila has provided considerable insight into the mechanisms controlling tissue growth and cell invasion/metastasis during tumourigenesis, as well as the importance of stem cells in tissue regeneration and cancer, and how genes cooperate in tumourigenesis. Several evolutionarily conserved signalling pathways are emerging as playing key roles in many of these processes, including the Jun kinase, Notch, Wnt, Jak/Stat and the Hippo tissue growth control pathway. Drosophila has also been specifically utilised to model certain human cancers, by expression of the human versions of cancer‐causing genes, including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia. Finally, the use of Drosophila as a vehicle for anticancer drug discovery is beginning to make an important impact in combating human cancer. Key Concepts: Drosophila is a useful system for modelling human cancer due to the high conservation of critical cancer‐causing genes between humans and flies. Many signalling pathways contribute to tissue growth; however, the Hippo growth control pathway is emerging as playing a major role. The Jun kinase signalling pathway plays a context‐dependent role in invasion/metastasis. Cell polarity and differentiation factors play important roles in controlling the behaviour of stem cells, which can be usurped in cancer. Cell competition mechanisms are important in removing damaged cells, and the perturbation of this control contributes to tumourigenesis. Cancer is a cooperative process and Drosophila research has revealed many cooperating oncogenes and tumour suppressors. Drosophila provides a useful model system to investigate specific human cancers including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia. Drosophila can be utilised to screen for anticancer drugs.

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Tumor suppression by cell competition through regulation of the Hippo pathway

Cited by 170 publications

References 33 publications

Epithelial neoplasia in Drosophila entails switch to primitive cell states

Epithelial neoplasia in Drosophila entails switch to primitive cell states

Mechanisms and mechanics of cell competition in epithelia

Modelling Cancer in Drosophila : The Next Generation

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