Human EWS-FLI protein levels and neomorphic functions show a complex, function-specific dose-response relationship in .

Ewing sarcoma (EwS) is a cancer that arises in the bones and soft tissues, typically driven by the Ewing's sarcoma breakpoint region 1-Friend leukemia virus integration 1 (EWS-FLI) oncogene. Implementation of genetically modified animal models of EwS has proved difficult largely owing to EWS-FLI's high toxicity. The EWS-FLI frameshift variant that circumvents toxicity but is still able to perform key oncogenic functions provided the first study model in .

TrxT and dhd are dispensable for Drosophila brain development but essential for l(3)mbt brain tumour growth.

Expression of the Drosophila cancer-germline (CG), X-linked, head-to-head gene pair TrxT and dhd is normally germline-specific but becomes upregulated in brain tumours caused by mutation in l(3)mbt. Here, we show that TrxT and dhd play a major synergistic role in the emergence of l(3)mbt tumour-linked transcriptomic signatures and tumour development, which is remarkable, taking into account that these two genes are never expressed together under normal conditions. We also show that TrxT, but not dhd, is crucial for the growth of l(3)mbt allografts, hence suggesting that the initial stages of tumour development and long-term tumour growth may depend on different molecular pathways.

Illuminati: a form of gene expression plasticity in Drosophila neural stem cells.

While testing for genome instability in Drosophila as reported by unscheduled upregulation of UAS-GFP in cells that co-express GAL80 and GAL4, we noticed that, as expected, background levels were low in most developing tissues. However, GFP-positive clones were frequent in the larval brain. Most of these clones originated from central brain neural stem cells.

Parafibromin governs cell polarity and centrosome assembly in Drosophila neural stem cells.

Neural stem cells (NSCs) divide asymmetrically to balance their self-renewal and differentiation, an imbalance in which can lead to NSC overgrowth and tumor formation. The functions of Parafibromin, a conserved tumor suppressor, in the nervous system are not established. Here, we demonstrate that Drosophila Parafibromin/Hyrax (Hyx) inhibits ectopic NSC formation by governing cell polarity.

Oxidative Stress Is Associated with Overgrowth in Drosophila Mutant Imaginal Discs.

The loss-of-function conditions for an () in larvae reared at 29 °C results in malignant brain tumours and hyperplastic imaginal discs. Unlike the former that have been extensively characterised, little is known about the latter. Here we report the results of a study of the hyperplastic mutant wing imaginal discs.

Structures of the germline-specific Deadhead and thioredoxin T proteins from reveal unique features among thioredoxins.

Thioredoxins (Trxs) are ubiquitous enzymes that regulate the redox state in cells. In , there are two germline-specific Trxs, Deadhead (Dhd) and thioredoxin T (TrxT), that belong to the lethal(3)malignant brain tumor signature genes and to the 'survival network' of genes that mediate the cellular response to DNA damage. Dhd is a maternal protein required for early embryogenesis that promotes protamine-histone exchange in fertilized eggs and midblastula transition.

Centrosomes in asymmetric cell division.

Asymmetric cell division (ACD) is a strategy for achieving cell diversity. Research carried out over the last two decades has shown that in some cell types that divide asymmetrically, mother and daughter centrosomes are noticeably different from one another in structure, behaviour, and fate, and that robust ACD depends upon centrosome function. Here, I review the latest advances in this field with special emphasis on the complex structure-function relationship of centrosomes with regards to ACD and on mechanistic insight derived from cell types that divide symmetrically but is likely to be relevant in ACD.

Context-Dependent Tumorigenic Effect of Testis-Specific Mitochondrial Protein in Drosophila Somatic Epithelia.

We have undertaken a study towards understanding the effect of ectopic expression of testis proteins in the soma in Drosophila. Here, we show that in the larval neuroepithelium, ectopic expression of the germline-specific component of the inner mitochondrial translocation complex () brings about cell autonomous hyperplasia and extension of G2 phase. In the wing discs, cells expressing ectopic upregulate Jun N-terminal kinase (JNK) signaling, present extended G2, become invasive, and elicit non-cell autonomous G2 extension and overgrowth of the wild-type neighboring tissue.

The histone code reader PHD finger protein 7 controls sex-linked disparities in gene expression and malignancy in .

The notable male predominance across many human cancer types remains unexplained. Here, we show that l(3)mbt brain tumors are more invasive and develop as malignant neoplasms more often in males than in females. By quantitative proteomics, we have identified a signature of proteins that are differentially expressed between male and female tumor samples.

Centrobin is essential for C-tubule assembly and flagellum development in spermatogenesis.

Centrobin homologues identified in different species localize on daughter centrioles. In sensory neurons, Centrobin (referred to as CNB in ) inhibits basal body function. These data open the question of CNB's role in spermatocytes, where daughter and mother centrioles become basal bodies.

Larval Brain Neoplasms Present Tumour-Type Dependent Genome Instability.

Single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) are found at different rates in human cancer. To determine if these genetic lesions appear in Drosophila tumors we have sequenced the genomes of 17 malignant neoplasms caused by mutations , , , or We have found CNVs and SNPs in all the tumors. Tumor-linked CNVs range between 11 and 80 per sample, affecting between 92 and 1546 coding sequences.

An genetic screen in identifies the orthologue of human cancer/testis gene among a network of targets to inhibit growth.

Using transgenic RNAi technology, we have screened over 4000 genes to identify targets to inhibit malignant growth caused by the loss of function of in We have identified 131 targets, which belong to a wide range of gene ontologies. Most of these target genes are not significantly overexpressed in mbt tumours hence showing that, rather counterintuitively, tumour-linked overexpression is not a good predictor of functional requirement. Moreover, we have found that most of the genes upregulated in mbt tumours remain overexpressed in tumour-suppressed double-mutant conditions, hence revealing that most of the tumour transcriptome signature is not necessarily correlated with malignant growth.

Prefoldin and Pins synergistically regulate asymmetric division and suppress dedifferentiation.

Prefoldin is a molecular chaperone complex that regulates tubulin function in mitosis. Here, we show that Prefoldin depletion results in disruption of neuroblast polarity, leading to neuroblast overgrowth in Drosophila larval brains. Interestingly, co-depletion of Prefoldin and Partner of Inscuteable (Pins) leads to the formation of gigantic brains with severe neuroblast overgrowth, despite that Pins depletion alone results in smaller brains with partially disrupted neuroblast polarity.

Arl2- and Msps-dependent microtubule growth governs asymmetric division.

Asymmetric division of neural stem cells is a fundamental strategy to balance their self-renewal and differentiation. It is long thought that microtubules are not essential for cell polarity in asymmetrically dividing Drosophila melanogaster neuroblasts (NBs; neural stem cells). Here, we show that Drosophila ADP ribosylation factor like-2 (Arl2) and Msps, a known microtubule-binding protein, control cell polarity and spindle orientation of NBs.

The translational relevance of Drosophila in drug discovery.

might be a suitable tool for drug discovery, but it is not clear how often the compounds identified will work in humans. A detailed look at previous work suggests that compounds active in both species might be relatively common. [Image: see text]

Studying tumor growth in Drosophila using the tissue allograft method.

This protocol describes a method to allograft Drosophila larval tissue into adult fly hosts that can be used to assay the tumorigenic potential of mutant tissues. The tissue of interest is dissected, loaded into a fine glass needle and implanted into a host. Upon implantation, nontransformed tissues do not overgrow beyond their normal size, but malignant tumors grow without limit, are invasive and kill the host.

Loss of Centrobin Enables Daughter Centrioles to Form Sensory Cilia in Drosophila.

Sensory cilia are organelles that convey information to the cell from the extracellular environment. In vertebrates, ciliary dysfunction results in ciliopathies that in humans comprise a wide spectrum of developmental disorders. In Drosophila, sensory cilia are found only in the neurons of type I sensory organs, but ciliary dysfunction also has dramatic consequences in this organism because it impairs the mechanosensory properties of bristles and chaetae and leads to uncoordination, a crippling condition that causes lethality shortly after eclosion.

Time-lapse recording of centrosomes and other organelles in Drosophila neuroblasts.

Drosophila larval neuroblasts (NBs) are an excellent model for asymmetric division and cell cycle studies in general. For decades, visualizing relevant structures like centrosomes, chromosomes, or the mitotic spindle relied exclusively on immunofluorescence on fix samples. More recently, improvements on sensitivity and acquisition speed of different confocal systems have made it possible to acquire time-resolved images of combined fluorescent reporters from single larval NBs.

Cayetano González: mothers, daughters, stemness, and cancer.

González studies centrosomal inheritance, asymmetric cell division, and cancer.

Quantitative differences, qualitative outcomes.

Fruit fly neuroblasts can either self-renew, rest or take on a specialized form, depending on the levels of a protein called Prospero.

When fate follows age: unequal centrosomes in asymmetric cell division.

A strong correlation between centrosome age and fate has been reported in some stem cells and progenitors that divide asymmetrically. In some cases, such stereotyped centrosome behaviour is essential to endow stemness to only one of the two daughters, whereas in other cases causality is still uncertain. Here, we present the different cell types in which correlated centrosome age and fate has been documented, review current knowledge on the underlying molecular mechanisms and discuss possible functional implications of this process.

The Brm-HDAC3-Erm repressor complex suppresses dedifferentiation in Drosophila type II neuroblast lineages.

The control of self-renewal and differentiation of neural stem and progenitor cells is a crucial issue in stem cell and cancer biology. Drosophila type II neuroblast lineages are prone to developing impaired neuroblast homeostasis if the limited self-renewing potential of intermediate neural progenitors (INPs) is unrestrained. Here, we demonstrate that Drosophila SWI/SNF chromatin remodeling Brahma (Brm) complex functions cooperatively with another chromatin remodeling factor, Histone deacetylase 3 (HDAC3) to suppress the formation of ectopic type II neuroblasts.