CR UK Cambridge Research Institute

Cambridge, United Kingdom

CR UK Cambridge Research Institute

Cambridge, United Kingdom
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Arias-Mendoza F.,Columbia University | Payne G.S.,Royal Marsden Hospital and Institute of Cancer Research | Zakian K.,Sloan Kettering Cancer Center | Stubbs M.,CR UK Cambridge Research Institute | And 17 more authors.
Academic Radiology | Year: 2013

Rationale and Objectives: Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging (31P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy. Experimental Design: The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using 31P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11months in eight patients, from 18 to 30months in three, and ≥60months in nine. Results: On a t test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at 6months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio=5.21, P < .02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF ≤ 11months (hazard ratio=8.66, P < .00001). Conclusions: The pretreatment tumor PME/NTP values correlated with response to treatment at 6months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients. © 2013 AUR.


Golinska M.,CR UK Cambridge Research Institute | Troy H.,St George's, University of London | Troy H.,Abbott Laboratories | Chung Y.-L.,St George's, University of London | And 19 more authors.
BMC Cancer | Year: 2011

Background: HIF-1 deficiency has marked effects on tumour glycolysis and growth. We therefore investigated the consequences of HIF-1 deficiency in mice, using the well established Hepa-1 wild-type (WT) and HIF-1β-deficient (c4) model. These mechanisms could be clinically relevant, since HIF-1 is now a therapeutic target.Methods: Hepa-1 WT and c4 tumours grown in vivo were analysed by 18FDG-PET and 19FDG Magnetic Resonance Spectroscopy for glucose uptake; by HPLC for adenine nucleotides; by immunohistochemistry for GLUTs; by immunoblotting and by DIGE followed by tandem mass spectrometry for protein expression; and by classical enzymatic methods for enzyme activity.Results: HIF-1β deficient Hepa-1 c4 tumours grew significantly more slowly than WT tumours, and (as expected) showed significantly lower expression of many glycolytic enzymes. However, HIF-1β deficiency caused no significant change in the rate of glucose uptake in c4 tumours compared to WT when assessed in vivo by measuring fluoro-deoxyglucose (FDG) uptake. Immunohistochemistry demonstrated less GLUT-1 in c4 tumours, whereas GLUT-2 (liver type) was similar to WT. Factors that might upregulate glucose uptake independently of HIF-1 (phospho-Akt, c-Myc) were shown to have either lower or similar expression in c4 compared to WT tumours. However the AMP/ATP ratio was 4.5 fold higher (p < 0.01) in c4 tumours, and phosphofructokinase-1 (PFK-1) activity, measured at prevailing cellular ATP and AMP concentrations, was up to two-fold higher in homogenates of the deficient c4 cells and tumours compared to WT (p < 0.001), suggesting that allosteric PFK activation could explain their normal level of glycolysis. Phospho AMP-Kinase was also higher in the c4 tumours.Conclusions: Despite their defective HIF-1 and consequent down-regulation of glycolytic enzyme expression, Hepa-1 c4 tumours maintain glucose uptake and glycolysis because the resulting low [ATP] high [AMP] allosterically activate PFK-1. This mechanism of resistance would keep glycolysis functioning and also result in activation of AMP-Kinase and growth inhibition; it may have major implications for the therapeutic activity of HIF inhibitors in vivo. Interestingly, this control mechanism does not involve transcriptional control or proteomics, but rather the classical activation and inhibition mechanisms of glycolytic enzymes. © 2011 Golinska et al; licensee BioMed Central Ltd.


Frye M.,Wellcome Trust Center for Stem Cell Research | Dragoni I.,CR UK Cancer Research Technology Ltd. | Chin S.-F.,CR UK Cambridge Research Institute | Spiteri I.,CR UK Cambridge Research Institute | And 12 more authors.
Cancer Letters | Year: 2010

We have examined expression of the Myc target gene Misu (NSUN2) in breast cancer. There was extensive copy number gain, and increased mRNA and protein levels, of Misu in approximately one third of breast cancer cell lines and primary tumours examined, irrespective of tumour subtype. Genes on 5p15.31-33, where Misu is located, showed evolutionary synteny. siRNA-mediated knockdown of Misu reduced cell number in over half of the cell lines tested, irrespective of estrogen receptor status. We conclude that Misu is up-regulated in a substantial proportion of breast cancers and has therapeutic potential as a drug target. © 2009 Elsevier Ireland Ltd. All rights reserved.


Hunziker L.,University College London | Hunziker L.,University of Basel | Benitah S.,University Pompeu Fabra | Braun K.M.,Center for Cutaneous Research | And 12 more authors.
PLoS ONE | Year: 2011

The thymic stroma supports T lymphocyte development and consists of an epithelium maintained by thymic epithelial progenitors. The molecular pathways that govern epithelial homeostasis are poorly understood. Here we demonstrate that deletion of Rac1 in Keratin 5/Keratin 14 expressing embryonic and adult thymic epithelial cells leads to loss of the thymic epithelial compartment. Rac1 deletion led to an increase in c-Myc expression and a generalized increase in apoptosis associated with a decrease in thymic epithelial proliferation. Our results suggest Rac1 maintains the epithelial population, and equilibrium between Rac1 and c-Myc may control proliferation, apoptosis and maturation of the thymic epithelial compartment. Understanding thymic epithelial maintenance is a step toward the dual goals of in vitro thymic epithelial cell culture and T cell differentiation, and the clinical repair of thymic damage from graft-versus-host-disease, chemotherapy or irradiation. © 2011 Hunziker et al.


Berta M.A.,CR UK Cambridge Research Institute | Baker C.M.,CR UK Cambridge Research Institute | Cottle D.L.,Wellcome Trust Center for Stem Cell Research | Watt F.M.,CR UK Cambridge Research Institute | Watt F.M.,Wellcome Trust Center for Stem Cell Research
EMBO Molecular Medicine | Year: 2010

Myc is activated in many tumours, yet, paradoxically, stimulates differentiation in mammalian epidermis. To test whether the epidermis responds differently to different levels of Myc, we treated K14MycER transgenic mice with a range of concentrations of the inducing agent, 4-hydroxy-tamoxifen (4OHT). Proliferation was stimulated at all levels of Myc activity; sebocyte differentiation was stimulated at low and intermediate levels; and interfollicular epidermal differentiation at intermediate and high levels. Mutational inactivation of the Myc p21 activated kinase 2 (PAK2) phosphorylation sites increased Myc activity and further enhanced epidermal differentiation. We conclude that Myc induced differentiation acts as a fail-safe device to prevent uncontrolled proliferation and neoplastic conversion of epidermal stem cells expressing high levels of Myc. © 2009 EMBO Molecular Medicine.


Storr S.J.,University of Nottingham | Mohammed R.A.A.,University of Nottingham | Mohammed R.A.A.,Assiut University | Woolston C.M.,University of Nottingham | And 7 more authors.
Breast | Year: 2011

Metastasis of breast cancer is a major contributor to mortality. Histological assessment of vascular invasion (VI) provides important prognostic information and demonstrates that VI occurs predominantly via lymphatics in breast cancer. We sought to examine genes and proteins involved in lymphovascular invasion (LVI) to understand the mechanisms of this key disease process. A gene expression array of 91 breast cancer patients was analysed by an Artificial Neural Network (ANN) approach using LVI to supervise the analysis. 89 transcripts were significantly associated (p < 0.001) with the presence of LVI. Calpastatin, a specific calpain inhibitor, had the second lowest selection error and was investigated in breast cancer specimens using real-time PCR (n = 56) and immunohistochemistry (n = 53). Both calpastatin mRNA and protein levels were significantly associated with the presence of LVI (p = 0.014 and p = 0.025 respectively). The data supports the hypothesis that calpastatin may play a role in regulating the initial metastatic dissemination of breast cancer. © 2011 Elsevier Ltd.


Hussain S.,University of Cambridge | Tuorto F.,German Cancer Research Center | Menon S.,CR UK Cambridge Research Institute | Blanco S.,University of Cambridge | And 6 more authors.
Molecular and Cellular Biology | Year: 2013

Posttranscriptional regulatory mechanisms are crucial for protein synthesis during spermatogenesis and are often organized by the chromatoid body. Here, we identify the RNA methyltransferase NSun2 as a novel component of the chromatoid body and, further, show that NSun2 is essential for germ cell differentiation in the mouse testis. In NSun2-depleted testes, genes encoding Ddx4, Miwi, and Tudor domain-containing (Tdr) proteins are repressed, indicating that RNA-processing and posttranscriptional pathways are impaired. Loss of NSun2 specifically blocked meiotic progression of germ cells into the pachytene stage, as spermatogonial and Sertoli cells were unaffected in knockout mice. We observed the same phenotype when we simultaneously deleted NSun2 and Dnmt2, the only other cytosine-5 RNA methyltransferase characterized to date, indicating that Dnmt2 was not functionally redundant with NSun2 in spermatogonial stem cells or Sertoli cells. Specific NSun2- and Dnmt2-methylated tRNAs decreased in abundance when both methyltransferases were deleted, suggesting that RNA methylation pathways play an essential role in male germ cell differentiation. © 2013, American Society for Microbiology.


Blanco S.,University of Cambridge | Kurowski A.,University of Cambridge | Nichols J.,University of Cambridge | Watt F.M.,University of Cambridge | And 3 more authors.
PLoS Genetics | Year: 2011

Homeostasis of most adult tissues is maintained by balancing stem cell self-renewal and differentiation, but whether post-transcriptional mechanisms can regulate this process is unknown. Here, we identify that an RNA methyltransferase (Misu/Nsun2) is required to balance stem cell self-renewal and differentiation in skin. In the epidermis, this methyltransferase is found in a defined sub-population of hair follicle stem cells poised to undergo lineage commitment, and its depletion results in enhanced quiescence and aberrant stem cell differentiation. Our results reveal that post-transcriptional RNA methylation can play a previously unappreciated role in controlling stem cell fate. © 2011 Blanco et al.


Nascimento E.M.,University of Cambridge | Cox C.L.,University of Cambridge | MacArthur S.,CR UK Cambridge Research Institute | Hussain S.,University of Cambridge | And 9 more authors.
Nature Cell Biology | Year: 2011

How the proto-oncogene c-Myc balances the processes of stem-cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Mycg's transcriptional roles at the epidermal differentiation complex, a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovol-1) and displace (Cebpa, Mxi1 and Sin3a) specific sets of differentiation-specific transcriptional regulators to epidermal differentiation complex genes. We found that Sin3a causes deacetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3a, genomic recruitment of c-Myc to the epidermal differentiation complex is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3a reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis through a negative feedback loop. © 2011 Macmillan Publishers Limited. All rights reserved.


PubMed | CR UK Cambridge Research Institute
Type: Journal Article | Journal: EMBO molecular medicine | Year: 2010

Myc is activated in many tumours, yet, paradoxically, stimulates differentiation in mammalian epidermis. To test whether the epidermis responds differently to different levels of Myc, we treated K14MycER transgenic mice with a range of concentrations of the inducing agent, 4-hydroxy-tamoxifen (4OHT). Proliferation was stimulated at all levels of Myc activity; sebocyte differentiation was stimulated at low and intermediate levels; and interfollicular epidermal differentiation at intermediate and high levels. Mutational inactivation of the Myc p21 activated kinase 2 (PAK2) phosphorylation sites increased Myc activity and further enhanced epidermal differentiation. We conclude that Myc induced differentiation acts as a fail-safe device to prevent uncontrolled proliferation and neoplastic conversion of epidermal stem cells expressing high levels of Myc.

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