1,721,074 research outputs found
MYC ectopic expression establishes a precancerous field leading to multifocal lesions in a Drosophila epithelial model
No full textThe term “field cancerisation” describes a precancerous area in which genetically altered but histologically normal tissues proceed towards the development of multiple malignant foci. In the early stages of tumour progression cells may indeed acquire genetic damages that allow them to proliferate in patches of altered cells gradually replacing normal tissue. This mechanism invokes MYC-mediated cell competition (MMCC), a phenomenon characterised in Drosophila consisting in fitness confrontation between cells sharing the same tissue, with cells expressing high MYC levels ultimately killing and replacing cells showing lower MYC activity. These intrinsic features of MMCC make it a candidate mechanism pioneering field cancerisation. Here we mimic field formation by upregulating MYC in a territory of the larval wing epithelium of Drosophila. Analysis of specific markers usually found in mammalian precancerous areas confirmed that MYC upregulation is sufficient to trigger specific cellular responses. Moreover, MYC-expressing fields were susceptible to the development of multifocal tumours upon induction of different second mutations, a typical trait correlated to mammalian field cancerisation. In summary, our study identified an undescribed early genetic change implicated in field cancerisation and established a genetically amenable model which may help study the molecular basis of the initial tumourigenic events
Nitric Oxide signaling disruption is associated with the maintenance of an undifferentiated status in imaginal tissues of D. melanogaster
No full textMYC, Cell Competition, and Cell Death in Cancer: The Inseparable Triad
Full text linkDeregulation of MYC family proteins in cancer is associated with a global reprogramming of gene expression, ultimately promoting glycolytic pathways, cell growth, and proliferation. It is well known that MYC upregulation triggers cell-autonomous apoptosis in normal tissues, while frankly malignant cells develop resistance to apoptotic stimuli, partly resulting from MYC addiction. As well as inducing cell-autonomous apoptosis, MYC upregulation is able to trigger non cell-autonomous apoptotic death through an evolutionarily conserved mechanism known as "cell competition". With regard to this intimate and dual relationship between MYC and cell death, recent evidence obtained in Drosophila models of cancer has revealed that, in early tumourigenesis, MYC upregulation guides the clonal expansion of mutant cells, while the surrounding tissue undergoes non-cell autonomous death. Apoptosis inhibition in this context was shown to restrain tumour growth and to restore a wild-type phenotype. This suggests that cell-autonomous and non cell-autonomous apoptosis dependent on MYC upregulation may shape tumour growth in different ways, soliciting the need to reconsider the role of cell death in cancer in the light of this new level of complexity. Here we review recent literature about MYC and cell competition obtained in Drosophila, with a particular emphasis on the relevance of cell death to cell competition and, more generally, to cancer. Possible implications of these findings for the understanding of mammalian cancers are also discussed
p53 Modulates MYC-Mediated Cell Competition in Different Cancer Contexts
No full textCell competition was originally described in Drosophila as a physiological process based on the comparison of relative fitness between neighbouring cells. At the end of the process, suboptimal cells, called losers, are committed to die while stimulating proliferation of the most performant cells, called winners, so maintaining tissue homeostasis. In Drosophila and mammalian development, cells showing high MYC activity behave like winners, growing at the expense of the surrounding cells which succumb by apoptosis, so unveiling a leading role for this oncoprotein in eliciting cell competition. Since MYC protein is upregulated in a large fraction of human cancers, cell competition has been speculated to play a role in human tumourigenesis. Consistently with this hypothesis, we found massive apoptotic death of stromal cells in proximity to MYC-upregulating cancer cells in a relevant number of human tumour samples, and showed that modulation of MYC activity in human cancer cell lines is sufficient to subvert their competitive drive. In Drosophila, MYC-overexpressing cells have been demonstrated to be unable to execute cell competition in a p53 loss-of-function background. With the aim to find a role for p53 in MYC-mediated cell competition, we first stained the same cancer samples as above for p53. Interestingly, the tumour regions that did not show significant signs of competitive interactions were also found negative for p53 staining, disclosing a possible function for this protein in promoting cancer-associated cell competition. Further experiments in a¬ Drosophila cancer model helped us define a dose-dependent role of p53 in MYC-overexpressing winner cells, and functional assays in co-cultures of human cancer cells confirmed that p53 function is necessary for the winner cells to execute cell competition. Altogether, our findings reveal a pro-oncogenic role of p53, that appears to cooperate with MYC in driving cell competition in different cancer contexts
MYC-Mediated Cell Competition as an Evolutionary Trait of Cancer
Full text linkMYC-Mediated Cell Competition (MMCC) is a phenomenon of fitness comparison occurring between
adjacent cells showing different levels of MYC activity.. It describes a mechanism, conserved from
Drosophila to mammalian development, through which cells characterised by high expression of MYC
induce apoptotic death of neighbouring low MYC-expressing cells and acquire an advantage in space
occupancy. Though it is widely speculated that this phenomenon is relevant to cancer, its characterisation
during tumour progression is still missing.
Here we show the presence of markers of MMCC in human carcinomas and demonstrate through
experiments in human cancer cell lines that MYC modulation is per se sufficient to induce competitive
behaviours in both genetically distant and identical cells. Noteworthy, MYC inhibition in the fittest cell line
is sufficient to reverse its competitive status. Moreover, data obtained in a Drosophila,cancer model indicate
that MMCC is normally at work during tumour growth and that induction of high or low-MYC expressing
cells in the growing masses deeply alters the final tumour size, supporting a role for MMCC in cancer
evolution
Functional Cooperation between p53 and MYC in Cancer-Associated Cell Competition
Full text linkCell competition is a mechanism conserved from Drosophila to mammals, based on the comparison of relative fitness between neighbouring cells, leading to the apoptotic elimination of the weakest. Several molecules are involved in these competitive interactions: in particular, cells expressing high levels of MYC grow at the expense of surrounding cells. In Drosophila epithelia, MYC-Mediated Cell Competition5 (MMCC) selects cells undergoing clonal expansion, and p53 function is necessary in MYC-overexpressing cells to sustain their competitive advantage. Malignant cells often upregulate MYC and results obtained in our lab suggest that MMCC can shape tumour expansion and evolution. p53 is one of the most frequently mutated genes in human cancers, with both loss and gain of function mutations playing roles in carcinogenesis. Through IHC analysis on several kinds of human carcinomas, in vitro co-culture assays and Drosophila experiments, we observed that loss of p53 in the winner cells is sufficient to make them unable to grow, thus suggesting a functional cooperation between MYC and p53 in cancer-associated MMCC. Our results show an oncogenic side of the p53 wild-type protein that appears to help shape cancer progression through selection of the most competitive cells
DROSOPHILA: THE CENTURY-LONG FLIGHT FROM THE WILD TO THE PATIENT
No full text: Background: Evolutionary conservation of key biological pathways between the fruit fly Drosophila melanogaster and humans and reduced genetic redundancy have long made flies a valuable genetic model organism. Thanks to the arsenal of sophisticated genetic tools developed and refined by the fly community, the use of Drosophila has expanded well beyond basic research. From the fundamental notion that genes are located on chromosomes to modeling human complex diseases such as cancer and neurological disorders, to designing fly "avatar" lines that precisely reproduce the specific mutations found in single cancer patients for personalized medicine, Drosophila continues to fuel biomedical advances. Numerous examples of drug testing in flies have yielded novel drug candidates, new uses for approved drugs, and applications for rapid drug optimization in modern approaches combining biology with medicinal chemistry. Thanks to the effectiveness of "fly pharmacology" approaches, Drosophila is also proficiently used to study the mechanism of action of environmental pollutants that represent a serious concern to human health. This review traces the history of some of the main advances in Drosophila biomedical and cancer research
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