ORCID Profile
0000-0003-4409-2421
Current Organisation
University of Bologna/ AIRC- Italian Association for Cancer Research
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Publisher: Elsevier BV
Date: 2022
DOI: 10.2139/SSRN.4015101
Publisher: Wiley
Date: 15-05-2021
DOI: 10.1002/JMV.27062
Abstract: Several severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants have emerged, posing a renewed threat to coronavirus disease 2019 containment and to vaccine and drug efficacy. In this study, we analyzed more than 1,000,000 SARS‐CoV‐2 genomic sequences deposited up to April 27, 2021, on the GISAID public repository, and identified a novel T478K mutation located on the SARS‐CoV‐2 Spike protein. The mutation is structurally located in the region of interaction with human receptor ACE2 and was detected in 11,435 distinct cases. We show that T478K has appeared and risen in frequency since January 2021, predominantly in Mexico and the United States, but we could also detect it in several European countries.
Publisher: MDPI AG
Date: 09-04-2021
Abstract: Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, lification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of ODC1, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype MYCN- lified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased ODC1 expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the ODC1 promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in MYCN- lified and non- lified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the ODC1 G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.
Publisher: Hindawi Limited
Date: 2017
DOI: 10.1155/2017/2690187
Abstract: Different 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 gene PTEN are very common in primary GBMs. Very recently, PTEN loss 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): PTEN loss 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 the Drosophila brain. Here we show that PTEN mutation impacts aPKC and Lgl protein levels also in Drosophila . 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.
Publisher: Elsevier BV
Date: 06-2020
DOI: 10.1016/J.SEMCANCER.2019.05.009
Abstract: Cancer has long been regarded and treated as a foreign body appearing by mistake inside a living organism. However, now we know that cancer cells communicate with neighbours, thereby creating modified environments able to support their unusual need for nutrients and space. Understanding the molecular basis of these bi-directional interactions is thus mandatory to approach the complex nature of cancer. Since their discovery, MYC proteins have been showing to regulate a steadily increasing number of processes impacting cell fitness, and are consistently found upregulated in almost all human tumours. Of interest, MYC takes part in cell competition, an evolutionarily conserved fitness comparison strategy aimed at detecting weakened cells, which are then committed to death, removed from the tissue and replaced by fitter neighbours. During physiological development, MYC-mediated cell competition is engaged to eliminate cells with suboptimal MYC levels, so as to guarantee selective growth of the fittest and proper homeostasis, while transformed cells expressing high levels of MYC coopt cell competition to subvert tissue constraints, ultimately disrupting homeostasis. Therefore, the interplay between cells with different MYC levels may result in opposite functional outcomes, depending on the nature of the players. In the present review, we describe the most recent findings on the role of MYC-mediated cell competition in different contexts, with a special emphasis on its impact on cancer initiation and progression. We also discuss the relevance of competition-associated cell death to cancer disease.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-01-2019
DOI: 10.1126/SCITRANSLMED.AAU1099
Abstract: MYCN regulates polyamines in neuroblastoma, and combined inhibition of polyamine synthesis and transport has therapeutic effects in mouse models.
Publisher: Cold Spring Harbor Laboratory
Date: 29-03-2021
DOI: 10.1101/2021.03.28.437369
Abstract: Several SARS-CoV-2 variants have emerged, posing a renewed threat to COVID-19 containment and to vaccine and drug efficacy. In this study, we analyzed more than 1,000,000 SARS-CoV-2 genomic sequences deposited up to April 27, 2021 on the GISAID public repository, and identified a novel T478K mutation located on the SARS-CoV-2 Spike protein. The mutation is structurally located in the region of interaction with human receptor ACE2 and was detected in 11,435 distinct cases. We show that T478K has appeared and risen in frequency since January 2021, predominantly in Mexico and USA, but we could also detect it in several European countries.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.BBAGRM.2018.01.007
Abstract: Childhood neuroblastoma, a disease of the sympathetic nervous system, is the most common solid tumour of infancy, remarkably refractory to therapeutic treatments. One of the most powerful independent prognostic indicators for this disease is the lification of the MYCN oncogene, which occurs at high levels in approximately 25% of neuroblastomas. Interestingly, lification and not just expression of MYCN has a strong prognostic value, although this fact appears quite surprising as MYCN is a transcription factor that requires dimerising with its partner MAX, to exert its function. This observation greatly suggests that the role of MYCN in neuroblastoma should be examined in the context of MAX expression. In this report, we show that, in contrast to what is found in normal cells, MAX expression is significantly different among primary NBs, and that its level appears to correlate with the clinical outcome of the disease. Importantly, controlled modulation of MAX expression in neuroblastoma cells with different extents of MYCN lification, demonstrates that MAX can instruct gene transcription programs that either reinforce or weaken the oncogenic process enacted by MYCN. In general, our work illustrates that it is the MAX to MYCN ratio that can account for tumour progression and clinical outcome in neuroblastoma and proposes that such a ratio should be considered as an important criterion to the design and development of anti-MYCN therapies.
Publisher: MDPI AG
Date: 17-04-2017
DOI: 10.3390/GENES8040120
Publisher: Springer Science and Business Media LLC
Date: 28-06-2021
DOI: 10.1038/S41467-021-24196-4
Abstract: MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN- lified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN- lified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2017
DOI: 10.1038/S41598-017-13002-1
Abstract: MYC-mediated cell competition is a cell-cell interaction mechanism known to play an evolutionary role during development from Drosophila to mammals. Cells expressing low levels of MYC, called losers , are committed to die by nearby cells with high MYC activity, called winners , that overproliferate to compensate for cell loss, so that the fittest cells be selected for organ formation. Given MYC’s consolidated role in oncogenesis, cell competition is supposed to be relevant to cancer, but its significance in human malignant contexts is largely uncharacterised. Here we show stereotypical patterns of MYC-mediated cell competition in human cancers: MYC-upregulating cells and apoptotic cells were indeed repeatedly found at the tumour-stroma interface and within the tumour parenchyma. Cell death amount in the stromal compartment and MYC protein level in the tumour were highly correlated regardless of tumour type and stage. Moreover, we show that MYC modulation in heterotypic co-cultures of human cancer cells is sufficient as to subvert their competitive state, regardless of genetic heterogeneity. Altogether, our findings suggest that the innate role of MYC-mediated cell competition in development is conserved in human cancer, with malignant cells using MYC activity to colonise the organ at the expense of less performant neighbours.
Publisher: Frontiers Media SA
Date: 11-12-2018
Location: Italy
No related grants have been discovered for SIMONE DI GIACOMO.