1,721,049 research outputs found
Gaucher Disease: a Hyper-Hippo Syndrome?
No full textThe Gaucher Disease (GD) is a lysosomal disorder associated with mutations in the GBA1 gene, encoding the acidic β-glucocerebrosidase. GD is characterized by a wide spectrum of phenotypic manifestations, the most severe of which involve the nervous system, with massive neuronal loss and microglial proliferation. Different symptoms are also observed in individuals bearing identical GBA1 mutations, suggesting that additional players are involved in the disease.
Our hypothesis is that hyper-activation of the Hippo pathway, recently found involved in some neurodegenerative syndromes, may contribute to the dramatic outcome of the neuronopathic GD. We thus started an expression analysis of upstream and downstream Hippo pathway components in Drosophila GBA1-deficient larval and adult organs.
While some Hippo downstream targets resulted down-regulated in GBA1-deficient tissues, both in terms of transcript and protein content, Fat, an atypical cadherin upstream of the kinase complex involved in the regulation of glial and synapse development, was found up-regulated. In the light of this latter result, we are currently performing behavioural assays in flies where GBA1 expression has been silenced in glial or neuronal cells, to find out possible cross-effects. Preliminary data will be presented about the implication of the Hippo pathway in the pathogenesis of the neuronopathic GD
A neurogenic model of adult brain cancer in the fly
No full textInactivation of the tumour suppressor gene PTEN is prevalent in primary Glioblastoma. In mammals, PTEN loss has been associated with the failure of a specific molecular axis, including aPKC and Lgl, responsible for the maintenance of the Glioblastoma Stem Cells (GSCs), a reservoir of self-sustaining cells with characteristics similar to neural progenitors.
Here we developed a neurogenic model of Drosophila brain cancer based on the dysfunction of the PTEN-aPKC-Lgl axis in type II neuroblasts (NB), whose differentiation proceeds through transit-amplifying intermediate precursors, as it is for mammalian neural progenitors. We obtained neurogenic tumours that express high levels of MYC, keep growing in the adult and lead the animal to premature death, summarising several traits typical of human brain cancers.
Recently, our laboratory has demostrated that the physiological phenomenon called MYC-Mediated Cell Competition (MMCC) is conserved in human cancers, where malignant cells are likely to use MYC activity to colonise the organ. Preliminary data will be presented about a possible correlation between MMCC and cell division in brain cancer development
A neurogenic model of adult brain cancer in Drosophila
No full textPrimary brain cancers are characterised by high cellular heterogeneity, with a subset of undifferentiated and highly tumourigenic cells responsible for cancer aggressiveness and relapse. Despite obvious anatomical differences between humans and flies, the structural and functional analogy of the respective nervous systems and the conservation of the cellular and molecular aberrations at the basis of the disease make Drosophila an excellent model for human brain cancer. Early inactivation of the tumour suppressor gene PTEN is frequent in primary glioblastoma, the most aggressive form of adult brain cancer whose origin is still controversial. This results in the inhibition of the polarity protein Lgl1 due to aPKC hyper-activation. Dysregulation of this molecular axis is sufficient to reprogramme human neural progenitors into cancer stem cells.
After having confirmed that the PTEN/aPKC/Lgl axis is conserved in Drosophila, we have disrupted it in type II neuroblasts, a cell population with a lineage comparable to that of mammalian neural stem cells, obtaining aggressive tumours that persist and keep growing in the adult leading the animals to premature death. This neurogenic model recapitulates many phenotypic traits of human brain cancers, included high proliferation rate, accumulation of undifferentiated neural cells, local invasiveness and genetic instability. Work in progress and future perspectives will also be presented
Failure of the PTEN/aPKC/Lgl Axis Primes Formation of Adult Brain Tumours in<i>Drosophila</i>
Full text linkDifferent regions in the mammalian adult brain contain immature precursors, reinforcing the concept that brain cancers, such as glioblastoma multiforme (GBM), may originate from cells endowed with stem-like properties. Alterations of the tumour suppressor genePTENare very common in primary GBMs. Very recently,PTENloss was shown to undermine a specific molecular axis, whose failure is associated with the maintenance of the GBM stem cells in mammals. This axis is composed of PTEN, aPKC, and the polarity determinant Lethal giant larvae (Lgl):PTENloss promotes aPKC activation through the PI3K pathway, which in turn leads to Lgl inhibition, ultimately preventing stem cell differentiation. To find the neural precursors responding to perturbations of this molecular axis, we targeted different neurogenic regions of theDrosophilabrain. Here we show thatPTENmutation impacts aPKC and Lgl protein levels also inDrosophila. Moreover, we demonstrate that PI3K activation is not sufficient to trigger tumourigenesis, while aPKC promotes hyperplastic growth of the neuroepithelium and a noticeable expansion of the type II neuroblasts. Finally, we show that these neuroblasts form invasive tumours that persist and keep growing in the adult, leading the affected animals to untimely death, thus displaying frankly malignant behaviours.</jats:p
Growth and Tracheogenesis are Separable Traits in Drosophila Cancers
No full textDrosophila clonal cancer models provide an excellent contribution to the study of the molecular basis of tumourigenesis. A number of human cancer hallmarks are indeed functionally conserved; among them, overgrowth and vessel remodelling are particularly relevant to primary mass formation and cell dissemination throughout the organism.
We have previously identified MYC as a Hippo downstream target in Drosophila and demonstrated that cells with defects in polarity genes require MYC expression to overwhelm wild-type neighbours and develop into malignant masses. Recent data from our lab also showed that neo-tracheogenesis does occur in Drosophila cancers, and it is either functionally or molecularly analogous to mammalian tumour neo-angiogenesis.
Here I extended on previous work showing that, in Drosophila epithelial tumours, mass expansion and tracheogenesis are separable traits, dependent on MYC and FOS activity respectively. These two transcription factors are found at the intersection of the Hippo, JNK and Ras/MAPK signalling cascades, which are recognised as central actors in cancer progression
High MYC Levels Favour Multifocal Carcinogenesis
Full text linkThe term “field cancerisation” describes the formation of tissue sub-areas highly susceptible to multifocal tumourigenesis. In the earlier stages of cancer, cells may indeed display a series of molecular alterations that allow them to proliferate faster, eventually occupying discrete tissue regions with irrelevant morphological anomalies. This behaviour recalls cell competition, a process based on a reciprocal fitness comparison: when cells with a growth advantage arise in a tissue, they are able to commit wild-type neighbours to death and to proliferate at their expense. It is known that cells expressing high MYC levels behave as super-competitors, able to kill and replace less performant adjacent cells; given MYC upregulation in most human cancers, MYC-mediated cell competition is likely to pioneer field cancerisation. Here we show that MYC overexpression in a sub-territory of the larval wing epithelium of Drosophila is sufficient to trigger a number of cellular responses specific to mammalian pre-malignant tissues. Moreover, following induction of different second mutations, high MYC-expressing epithelia were found to be susceptible to multifocal growth, a hallmark of mammalian pre-cancerous fields. In summary, our study identified an early molecular alteration implicated in field cancerisation and established a genetically amenable model which may help study the molecular basis of early carcinogenesis
Drosophila melanogaster: a model organism to study cancer
Full text linkCancer is a multistep disease driven by the activation of specific oncogenic pathways,
concomitantly, with the suppression of tumor suppressor genes that act as sentinels to
control physiological growth. The conservation of most of these signaling pathways in
Drosophila, and the ability to easily manipulate them genetically, has made the fruit fly
a useful model organism to study cancer biology. In this review we outlined the basic
mechanisms and signaling pathways, conserved between humans and flies, responsible
for inducing uncontrolled growth, and cancer development. Second, we described
classic and novel Drosophila models used to study different cancers, with the objective to
discuss the strengths and limitations of their use, to understand cell growth autonomously
and within organs, and to discuss their use in drug screening aimed at discovering
therapeutic approaches
Cancer cells contribute to distinct malignant traits depending on their MYC and pJNK relative levels
No full textClonal analysis is common practice in Drosophila. In particular, induction of cell clusters carrying either loss-of-function alleles of neoplastic tumour suppressors or activated forms of oncogenes has successfully been exploited to study cooperative tumourigenesis in different organs. This strategy has allowed collecting a number of morphological and molecular details on the phenotypic traits associated with cancer progression. We previously identified MYC as a target of the Hippo pathway in Drosophila, and showed its expression is sufficient as to rescue the growth deficit of cells mutant for polarity genes, releasing their malignant nature. Here we expand on previous work, showing that cell growth and cell migration are separable traits in Drosophila epithelial cancers. While in situ cancer expansion is supported by MYC, migration depends on the AP-1 protein Fos. These proteins are strategically found at the crossroads of the Hippo, JNK and Ras/MAPK pathways, acknowledged by current literature as central players in cancer progression. Moreover, we show that growth and migration are mutually exclusive behaviours, with cells displaying different MYC and pJNK levels playing distinct roles in cancer evolution
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