Cancer in Drosophila

Herranz, Héctor; Eichenlaub, Teresa; Cohen, Stephen M.

doi:10.1016/bs.ctdb.2015.11.037

Cited by 47 publications

(33 citation statements)

References 111 publications

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“…Abnormal signalling has been widely reported in a many cancer types across species [ 1 , 47 , 48 ]. It is clear that cancer cells can utilize signalling modules to obtain growth advantage and invade healthy tissues, but it is often difficult to tease apart whether this is a consequence of transformation or an intrinsic feature of tumour onset.…”

Section: Discussionmentioning

confidence: 99%

“…These include loss of cell polarity, compromised epithelial architecture and oncogenic cooperation. For instance, activation of known tumour drivers such as Ras, Notch, Myc or EGFR lead to benign hyperplasia in imaginal discs, but in combination with loss of epithelial integrity result in neoplastic growth [ 1 – 4 ]. Epithelial tumours in humans also lose polarity as they acquire malignant properties, pointing towards the importance of altered cellular interactions for disease progression in tissues harbouring pre-cancerous lesions.…”

Section: Introductionmentioning

confidence: 99%

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Signalling crosstalk during early tumorigenesis in the absence of Polycomb silencing

2018

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In response to stress and injury a coordinated activation of conserved signalling modules, such as JNK and JAK/STAT, is critical to trigger regenerative tissue restoration. While these pathways rebuild homeostasis and promote faithful organ recovery, it is intriguing that they also become activated in various tumour conditions. Therefore, it is crucial to understand how similar pathways can achieve context-dependent functional outputs, likely depending on cellular states. Compromised chromatin regulation, upon removal of the Polycomb group member polyhomeotic, leads to tumour formation with ectopic activation of JNK signalling, mediated by egr/grnd, in addition to JAK/STAT and Notch. Employing quantitative analyses, we show that blocking ectopic signalling impairs ph tumour growth. Furthermore, JAK/STAT functions in parallel to JNK, while Notch relies on JNK. Here, we reveal a signalling hierarchy in ph tumours that is distinct from the regenerative processes regulated by these pathways. Absence of ph renders a permissive state for expression of target genes, but our results suggest that both loss of repression and the presence of activators may collectively regulate gene expression during tumorigenesis. Further dissecting the effect of signalling, developmental or stress-induced factors will thus elucidate the regulation of physiological responses and the contribution of context-specific cellular states.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Signalling crosstalk during early tumorigenesis in the absence of Polycomb silencing

2018

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“…Carcinomas originating in epithelial tissues are among the most common human cancers. The Drosophila imaginal discs are epithelial monolayers that proliferate actively during larval development, and have proven to be a useful model to study epithelial tumor formation (reviewed in Herranz et al, 2016 ). Overexpression of Yorkie (Yki), the fly ortholog of the YAP oncoprotein, leads to benign epithelial hyperplasia without driving the tissue into neoplasia ( Dong et al, 2007 ; Herranz et al, 2012a ; Huang et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

The chromatin remodeling BAP complex limits tumor promoting activity of the Hippo pathway effector Yki to prevent neoplastic transformation inDrosophilaepithelia

Song

Herranz

Cohen

2017

Disease Models &Amp; Mechanisms

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Switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes are mutated in many human cancers. In this article, we make use of a Drosophila genetic model for epithelial tumor formation to explore the tumor suppressive role of SWI/SNF complex proteins. Members of the BAP complex exhibit tumor suppressor activity in tissue overexpressing the Yorkie (Yki) proto-oncogene, but not in tissue overexpressing epidermal growth factor receptor (EGFR). The Brahma-associated protein (BAP) complex has been reported to serve as a Yki-binding cofactor to support Yki target expression. However, we observed that depletion of BAP leads to ectopic expression of Yki targets both autonomously and non-autonomously, suggesting additional indirect effects. We provide evidence that BAP complex depletion causes upregulation of the Wingless (Wg) and Decapentaplegic (Dpp) morphogens to promote tumor formation in cooperation with Yki.

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“…Increased HMGA2 has been shown to induce genomic instability by interfering with nonhomologous end-joining function and delaying clearance of markers of DNA damage, including γ-H2AX (Li et al, 2009). As the creation of genomic instability induces apoptosis in many cell types (Herranz, Eichenlaub, & Cohen, 2016), we believe that this increased HMGA2 could explain the increased apoptosis. However, when we immunostained the BRCA1 knockout cells for γ-H2AX immunoreactivity we were unable to determine a significant difference in DNA damage compared with In normal, differentiated placental cells the BRCA1/ZNF350/CtIP repressor complex forms and binds to the promoter region of HMGA2 to prevent transcription.…”

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confidence: 87%

BRCA1 regulates HMGA2 levels in the Swan71 trophoblast cell line

West

Russ

Bouma

et al. 2019

Molecular Reproduction Devel

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During early placental development, tumor suppressors and oncogenes work synergistically to regulate cell proliferation and differentiation in a restrained manner compared with the uncontrollable growth in cancer. One example of this partnership is the regulation of the oncofetal protein HMGA2 by BRCA1. BRCA1 forms a repressor complex with ZNF350 and CtIP to bind to the promoter of HMGA2, preventing transcription. Chromatin immunoprecipitation determined BRCA1 forms this repressor complex in human trophoblast cells, suggesting a role in the placenta. Furthermore, miR‐182 has been shown to target BRCA1 mRNA in ovarian cancer cells, blocking the formation of the BRCA1 repressor complex and allowing increased transcription of HMGA2. miR‐182 was one of the first miRNAs described as elevated in the serum and placentas of preeclamptic women. Therefore, we hypothesized that BRCA1 is essential for normal trophoblast cell development. We used CRISPR‐Cas9 genome editing and miR‐182 overexpression to decrease BRCA1 protein in the Swan71 cell line. HMGA2 was significantly increased in the BRCA1 KO and miR‐182 overexpressing cells compared to controls. We also determined that BRCA1 repressor complex binding to HMGA2 was significantly reduced in BRCA1 KO and miR‐182 overexpressing cells compared with controls, leading us to conclude that increased HMGA2 was because of decreased binding of the BRCA1 repressor complex. Finally, we found that the caspase activity was significantly higher in BRCA1 KO and miR‐182 overexpressing cells suggesting an increased amount of apoptosis. These data suggest that BRCA1 is an important regulator of the oncofetal protein HMGA2 and promotes cell survival in human placental cells.

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Cancer in Drosophila

Cited by 47 publications

References 111 publications

Signalling crosstalk during early tumorigenesis in the absence of Polycomb silencing

Signalling crosstalk during early tumorigenesis in the absence of Polycomb silencing

The chromatin remodeling BAP complex limits tumor promoting activity of the Hippo pathway effector Yki to prevent neoplastic transformation inDrosophilaepithelia

BRCA1 regulates HMGA2 levels in the Swan71 trophoblast cell line

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