A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth

Mayrhofer, Marie; Gourain, Victor; Reischl, Markus; Affaticati, Pierre; Jenett, Arnim; Joly, Jean Stéphane; Benelli, Matteo; Demichelis, Francesca; Poliani, Pietro Luigi; Sieger, Dirk; Mione, Marina

doi:10.1242/dmm.026500

Cited by 61 publications

(89 citation statements)

References 79 publications

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“…Samples were subjected to tissue clearing following CLARITY/PACT protocol, with some tissue‐specific adaptations (Chung et al, ; Mayrhofer et al, ; Treweek et al, ): dissected brains were fixed in freshly prepared ice‐cold methanol‐free PFA 4% in PBS (pH 7.4) overnight at 4°C. Samples were then infused in a precooled solution of freshly prepared hydrogel monomers (0.01 M PBS, 0.25% VA‐044 initiator, 5% dimethyl sulfoxide, 1% PFA, 4% acrylamide, and 0.0025% bis‐acrylamide) for 2 days at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Comparative analysis of monoaminergic cerebrospinal fluid‐contacting cells in Osteichthyes (bony vertebrates)

Xavier

Fontaine

Bloch

et al. 2017

J of Comparative Neurology

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Cerebrospinal fluid-contacting (CSF-c) cells containing monoamines such as dopamine (DA) and serotonin (5-HT) occur in the periventricular zones of the hypothalamic region of most vertebrates except for placental mammals. Here we compare the organization of the CSF-c cells in chicken, Xenopus, and zebrafish, by analyzing the expression of synthetic enzymes of DA and 5-HT, respectively, tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), and draw an evolutionary scenario for this cell population. Due to the lack of TH immunoreactivity in this region, the hypothalamic CSF-c cells have been thought to take up DA from the ventricle instead of synthesizing it. We demonstrate that a second TH gene (TH2) is expressed in the CSF-c cells of all the three species, suggesting that these cells do indeed synthetize DA. Furthermore, we found that many CSF-c cells coexpress TH2 and TPH1 and contain both DA and 5-HT, a dual neurotransmitter phenotype hitherto undescribed in the brain of any vertebrate. The similarities of CSF-c cells in chicken, Xenopus, and zebrafish suggest that these characteristics are inherited from the common ancestor of the Osteichthyes. A significant difference between tetrapods and teleosts is that teleosts possess an additional CSF-c cell population around the posterior recess (PR) that has emerged in specific groups of Actinopterygii. Our comparative analysis reveals that the hypothalamus in mammals and teleosts has evolved in a divergent manner: placental mammals have lost the monoaminergic CSF-c cells, while teleosts have increased their relative number. K E Y W O R D S

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Section: Methodsmentioning

confidence: 99%

Comparative analysis of monoaminergic cerebrospinal fluid‐contacting cells in Osteichthyes (bony vertebrates)

Xavier

Fontaine

Bloch

et al. 2017

J of Comparative Neurology

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“…For instance, Mione and colleagues established a novel brain tumor model using HRAS V12 in which increased brain size was observed already at 3 dpf (Mayrhofer et al, 2017). Activating the β-catenin signal promotes liver enlargement associated with enhanced proliferation at 6 dpf in the model established by Stainier and colleagues (Evason et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in tumor's adverse effects on host

Enya

Kawakami

Suzuki

et al. 2018

Disease Models &Amp; Mechanisms

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The nature of host organs and genes that underlie tumor-induced physiological disruption on the host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is suitable for addressing this issue, and find that hepatic cyp7a1, the rate-limiting factor for synthesizing bile acids [or, in the case of zebrafish, bile alcohol (BA)], is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in the formation of an intestinal tumor. The local intestinal tumor caused systemic detrimental effects on the host, including liver inflammation, hepatomegaly, growth defects and organismal death. Whole-organism-level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BA levels, possibly via altered expression of hepatic cyp7a1. Genetically overexpressing cyp7a1 in the liver restored BA synthesis and ameliorated tumor-induced liver inflammation, but not other tumor-dependent phenotypes. Thus, we found a previously unknown role of cyp7a1 as the host gene that links the intestinal tumor, hepatic cholesterol–BA metabolism and liver inflammation in tumor-bearing zebrafish larvae. Our model provides an important basis to discover host genes responsible for tumor-induced phenotypes and to uncover mechanisms underlying how tumors adversely affect host organisms.

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“…We recently developed a zebrafish model of brain cancer, which is based on the injection of a plasmid encoding for UAS driven GFP-tagged HRAS G12V in one-cell stage embryos of a transgenic line expressing the transactivator Gal4 in neural progenitor cells, Et(zic4:Gal4TA4, UAS:mCherry) hzm5 , here called zic:Gal4. This leads to the integration and expression of the oncogene in a few neural progenitor cells, that become cancer-initiating cells 30 . In order to investigate telomere length in zebrafish brain tumors we used 1-2 month (m) old zebrafish with RAS-induced brain tumors, here called RAS, and performed terminal restriction fragment (TRF) analysis followed by Southern blot.…”

Section: Telomeres In Zebrafish Brain Tumours Are Long and Heterogeneousmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Recently, we generated a zebrafish model of brain tumors based on somatic expression of human oncogenes 30 . In this model, brain tumors resemble the molecular mesenchymal subtype of glioblastoma 30 . Here we investigated the telomere maintenance mechanism adopted by brain tumor cells in this zebrafish model of brain cancer and found that brain cancer cells progressively develop ALT, upon reduction of telomerase expression and activity and increase of TERRA levels.…”

Section: Introductionmentioning

confidence: 99%

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Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors

Idilli

Cusanelli

Pagani

et al. 2019

Preprint

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The activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear.Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT.We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks at chromosome ends. Surprisingly, expression of telomerase reverts ALT features. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed increase of telomeric heterochromatin and maintenance of telomere length compared to ALT tumors, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of telomeric DNA replication and chromatin status in brain cancers. of cancers use alternative lengthening of telomeres (ALT), a mechanism based on homologous recombination between telomeres 3 . The molecular details of ALT activation remain to be defined 4 . ALT is found mostly in tumors with a mesenchymal origin (sarcoma) and in a subset of malignant paediatric brain tumors 5 , including High Grade Glioma (HGG, 51%), Diffuse Intrinsic Pontine Glioma (DIPG) (18%), Choroid Plexus Carcinoma (CPC) (22.6%), and Primitive Neuroectodermal Tumors (PNET) (11.6%) 6,7 . HGGs represent approximately 3-5% of childhood brain tumors and include a heterogeneous group of rare but aggressive tumors 8 , which remains largely incurable, with the most aggressive forms being lethal within months. In contrast with adult glioma, mutations within the promoter region of the telomerase catalytic subunit, TERT, occur at a lower rate in paediatric tumors (3-11% compared to 55-83% in adult tumors) 9 . Indeed, paediatric gliomas show distinctive genetic mutations, which suggest that the mechanisms of tumor development and progression are different from those identified in adult brain tumors, where ALT develops in approximately 15% of cases, and associates with IDH1 mutations and better prognosis 10 .Exon sequencing of paediatric HGGs identified recurrent somatic mutations (K27M, G34R/V) in histone H3 11,12 , and inactivating mutations in the Death-domain associated protein/Alpha thalassemia-mental retardation (DAXX/ATRX) genes, leading to DNA hypomethylation 13,14,15 .These findings suggest that telomeric chromatin plays an important role in ALT. Altered histone modifications in subtelomeric regions in association with ATRX loss result in deregulated telomere length and chromosomal instability, features that are often associated with ALT 4 . Notably, ALT activation can be inferred by a number of other features, including the presence of heterogeneous telomeres, w...

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A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth

Cited by 61 publications

References 79 publications

Comparative analysis of monoaminergic cerebrospinal fluid‐contacting cells in Osteichthyes (bony vertebrates)

Comparative analysis of monoaminergic cerebrospinal fluid‐contacting cells in Osteichthyes (bony vertebrates)

A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in tumor's adverse effects on host

Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors

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