Institute of Cancer Research ICR
Institute of Cancer Research ICR
Castellano L.,Imperial College London |
Dabrowska A.,Imperial College London |
Pellegrino L.,Institute of Cancer Research ICR |
Ottaviani S.,Imperial College London |
And 4 more authors.
Nucleic Acids Research | Year: 2017
MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a overexpressing cells partially rescues normalmitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA. © The Author(s) 2017.
Loriot Y.,University Paris - Sud |
Fizazi K.,University Paris - Sud |
Jones R.J.,University of Glasgow |
Van Den Brande J.,University of Antwerp |
And 9 more authors.
Investigational New Drugs | Year: 2014
Summary Background: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated antitumour activity in in vitro and in vivo preclinical models. Material and methods: This first-in-man phase I/II study utilised a 3+3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed. Results: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N=5), constipation (N=4), diarrhoea (N=3), back pain (N=3) and cancer pain (N=3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part. Conclusions: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity. © Springer Science+Business Media 2014.
Robertson L.B.,Institute of Cancer Research ICR |
Armstrong G.N.,University of Texas M. D. Anderson Cancer Center |
Olver B.D.,Institute of Cancer Research ICR |
Lloyd A.L.,Institute of Cancer Research ICR |
And 28 more authors.
Familial Cancer | Year: 2010
There is increasing recognition of familial propensity to glioma as a distinct clinical entity beyond a few rare syndromes; however its genetic basis is poorly understood. The role of p16INK4A/p14ARF and p53 mutations in sporadic glioma provides a strong rationale for investigating germline mutations in these genes as a cause of familial glioma. To survey the familial glioma phenotype and examine the contribution of germline mutation in p16INK4A/p14ARF and p53 to the disease we have analyzed a series of 101 index familial cases collected through the GLIOGENE Consortium (http://braintumor. epigenetic.org/). There was little evidence for within family correlations for tumour histology, suggesting generic susceptibility to glial tumors. We did not detect any functional mutations in p16INK4A or p14ARF. One index case with glioblastoma multiforme (GBM) diagnosed at age 54 and had a family history comprised of a paternal aunt with GBM at age 55, carried the p53 R158H mutation, which is predicted to be functional and has previously been implicated as a cause of Li-Fraumeni syndrome. Our findings provide no evidence that p16INK4A/p14 ARF and p53 mutations contribute significantly to familial glioma. © Springer Science+Business Media B.V. 2010.
Sadanandam A.,Swiss Institute of Bioinformatics |
Sadanandam A.,Ecole Polytechnique Federale de Lausanne |
Sadanandam A.,Institute of Cancer Research ICR |
Wullschleger S.,Ecole Polytechnique Federale de Lausanne |
And 16 more authors.
Cancer Discovery | Year: 2015
Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/ insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. Significance: This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. © 2015 American Association for Cancer Research.
Tatton-Brown K.,St George's, University of London |
Tatton-Brown K.,Royal Marsden Hospital |
Rahman N.,Institute of Cancer Research ICR
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2013
NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2 is a major proto-oncogene and mono- and biallelic activating and inactivating somatic mutations occur as early events in the development of tumors, particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains. EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Many additional questions about the molecular and clinical features of NSD1 and EZH2 remain unanswered. However, studies are underway to address these and, as more cases are ascertained and technology improves, it is hoped that these will, in time, be answered. © 2013 Wiley Periodicals, Inc.
Tan C.S.H.,Samuel Lunenfeld Research Institute |
Tan C.S.H.,University of Toronto |
Jorgensen C.,Institute of Cancer Research ICR |
Linding R.,Institute of Cancer Research ICR
Cell Cycle | Year: 2010
Protein phosphorylation dynamically regulates cellular activities in response to environmental cues. Sequence conservation analysis of recent proteome-wide phosphorylation data revealed that many previously unidentified phosphorylation sites are not well-conserved leading to the proposal that many are non-functional. However, this is based on the assumption that protein phosphorylation modulates protein function through specific position on protein sequence. Based on emerging understanding on phosphoregulation of cellular activities, we argue, with examples, that non-positionally conserved phosphorylation sites can very well be functional. We previously identified phosphorylation events that need not be conserved at same positions across orthologous proteins but are likely maintained by evolutionary conserved signaling networks through orthologous kinases. We found that proteins with such conserved phosphorylation patterns are statistically over-represented with protein and DNA-binding annotation. Here, we further correlated these proteins with protein-protein interaction data from an independent systematic study and observed they indeed interact frequently with other proteins. Hence, we speculate that non-positionally conserved phosphorylation site could be modulating biomolecular association of phosphorylated proteins possibly through fine-tuning protein's bulk electrostatic charge and through creating binding sites for phospho-binding interaction domains. We, therefore, advocate the development of complementary evolutionary approaches to interpret physiological important sites. © 2010 Landes Bioscience.
Jasnos L.,Institute of Cancer Research ICR |
Sawado T.,Institute of Cancer Research ICR
Nature Protocols | Year: 2014
Symmetric cell divisions give rise to two sister cells that are identical to each other, whereas asymmetric divisions produce two sister cells with distinctive phenotypes. Although cell division symmetry is usually determined on the basis of a few markers or biological functions, the overall similarity between sister cells has not been thoroughly examined at a molecular level. Here we provide a protocol to separate sister embryonic stem cells (ESCs) and to conduct multiplexed gene expression analyses at the single-cell level by using 48 ESC genes. The procedure includes the dissection of dividing, paired sister cells by micromanipulation, followed by cell lysis, reverse transcription, gene-specific cDNA amplification and multiplexed quantitative PCR analyses. This protocol can be completed in 10 d, and it can be readily adapted to other cell types that are able to grow in suspension culture. © 2014 Nature America, Inc.
Erler J.T.,Institute of Cancer Research ICR |
Linding R.,Institute of Cancer Research ICR
Journal of Pathology | Year: 2010
The structure and dynamics of protein signalling networks governs cell decision processes and the formation of tissue boundaries. Complex diseases such as cancer and diabetes are diseases of such networks. Therefore approaches that can give insight into how these networks change during disease progression are crucial for better understanding, detection and intervention. The era of network medicine has begun; however, there are fundamental principles associated with molecular networks that are essential to consider for this field to succeed. Here, we introduce network biology and some of its associated technologies. We then focus on the multivariate nature of cellular networks and how this has implications for biomarker and drug discovery using cancer metastasis as an example. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Biswas S.,Northumbria University |
Wood M.,Northumbria University |
Joshi A.,Northumbria University |
Bown N.,Northumbria University |
And 5 more authors.
Frontiers in Oncology | Year: 2015
Atypical teratoid rhabdoid tumors (AT/RTs) are rare pediatric brain tumors characterized by bialleic loss of the SMARCB1 tumor suppressor gene. In contrast to pediatric AT/RT that has a simple genome, very little is known about the adult AT/RT genomic landscape. Using a combination of whole-exome sequencing and high-resolution SNP array in a single adult pituitary AT/RT, we identified a total of 47 non-synonymous mutations, of which 20 were predicted to cause non-conservative amino acid substitutions, in addition to a subclone of cells with trisomy 8. We suggest that adult AT/RT may not be markedly dissimilar to other adult brain tumors where mutations in a range of genes, reflecting the functional specialization of different brain regions, but including SMARCB1 inactivation, may be required for its pathogenesis. © 2015 Biswas, Wood, Joshi, Bown, Strain, Martinsson, Campbell, Ashworth and Swain.