Theodor Boveri Institute

Schönau am Königssee, Germany

Theodor Boveri Institute

Schönau am Königssee, Germany

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Bensaad K.,Weatherall Institute of Molecular Medicine | Favaro E.,Weatherall Institute of Molecular Medicine | Lewis C.A.,Cancer Research UK Research Institute | Lewis C.A.,Massachusetts Institute of Technology | And 15 more authors.
Cell Reports | Year: 2014

An invivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. Invitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected tohypoxia-reoxygenation invitro, and strongly impaired tumorigenesis invivo. © 2014 The Authors.


Cannell I.G.,University of Nottingham | Kong Y.W.,University of Nottingham | Johnston S.J.,University of Nottingham | Chen M.L.,University of Nottingham | And 11 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

The DNA damage response activates several pathways that stall the cell cycle and allow DNA repair. These consist of the well-characterized ATR (Ataxia telangiectasia and Rad-3 related)/ CHK1 and ATM (Ataxia telangiectasia mutated)/CHK2 pathways in addition to a newly identified ATM/ATR/p38MAPK/MK2 checkpoint. Crucial to maintaining the integrity of the genome is the Sphase checkpoint that functions to prevent DNA replication until damaged DNA is repaired. Inappropriate expression of the proto-oncogene c-Myc is known to cause DNA damage. One mechanism by which c-Myc induces DNA damage is through binding directly to components of the prereplicative complex thereby promoting DNA synthesis, resulting in replication-associated DNA damage and checkpoint activation due to inappropriate origin firing. Here we show that following etoposide-induced DNA damage translation of c-Myc is repressed by miR-34c via a highly conserved target-site within the 3′ UTR. While miR-34c is induced by p53 following DNA damage, we show that in cells lacking p53 this is achieved by an alternative pathway which involves p38 MAPK signalling to MK2. The data presented here suggest that a major physiological target of miR-34c is c-Myc. Inhibition of miR-34c activity prevents S-phase arrest in response to DNA damage leading to increased DNA synthesis, DNA damage, and checkpoint activation in addition to that induced by etoposide alone, which are all reversed by subsequent c-Myc depletion. These data demonstrate that miR-34c is a critical regulator of the c-Myc expression following DNA damage acting downstream of p38 MAPK/MK2 and suggest that miR-34c serves to remove c-Myc to prevent inappropriate replication which may otherwise lead to genomic instability.


Iraci N.,University of Bologna | Diolaiti D.,University of Bologna | Diolaiti D.,Fred Hutchinson Cancer Research Center | Papa A.,University of Bologna | And 10 more authors.
Cancer Research | Year: 2011

Neuroblastoma is the most common extracranial solid tumor of childhood. One important factor that predicts a favorable prognosis is the robust expression of the TRKA and p75NTR neurotrophin receptor genes. Interestingly, TRKA and p75NTR expression is often attenuated in aggressive MYCN-amplified tumors, suggesting a causal link between elevated MYCN activity and the transcriptional repression of TRKA and p75NTR, but the precise mechanisms involved are unclear. Here, we show that MYCN acts directly to repress TRKA and p75NTR gene transcription. Specifically, we found that MYCN levels were critical for repression and that MYCN targeted proximal/core promoter regions by forming a repression complex with transcription factors SP1 and MIZ1. When bound to the TRKA and p75NTR promoters, MYCN recruited the histone deacetylase HDAC1 to induce a repressed chromatin state. Forced re-expression of endogenous TRKA and p75NTR with exposure to the HDAC inhibitor TSA sensitized neuroblastoma cells to NGF-mediated apoptosis. By directly connecting MYCN to the repression of TRKA and p75NTR, our findings establish a key pathway of clinical pathogenicity and aggressiveness in neuroblastoma. © 2010 American Association for Cancer Research.


Ceteci F.,Max Planck Institute of Biochemistry | Xu J.,Theodor Boveri Institute | Ceteci S.,Max Planck Institute of Biochemistry | Zanucco E.,Max Planck Institute of Biochemistry | And 2 more authors.
Neoplasia | Year: 2011

Here we describe a novel conditional mouse lung tumor model for investigation of the pathogenesis of human lung cancer. On the basis of the frequent involvement of the Ras-RAF-MEK-ERK signaling pathway in human non-small cell lung carcinoma (NSCLC), we have explored the target cell availability, reversibility, and cell type specificity of transformation by oncogenic C-RAF. Targeting expression to alveolar type II cells or to Clara cells, the two likely precursors of human NSCLC, revealed differential tumorigenicity between these cells. Whereas expression of oncogenic C-RAF in alveolar type II cells readily induced multifocal macroscopic lung tumors independent of the developmental state, few tumors with type II pneumocytes features and incomplete penetrance were found when targeted to Clara cells. Induced tumors did not progress and were strictly dependent on the initiating oncogene. Deinduction of mice resulted in tumor regression due to autophagy rather than apoptosis. Induction of autophagic cell death in regressing lung tumors suggests the use of autophagy enhancers as a treatment choice for patients with NSCLC. © 2011 Neoplasia Press, Inc. All rights reserved.


Stock M.,University of Lausanne | Lampert K.P.,Ruhr University Bochum | Moller D.,University of Hamburg | Schlupp I.,University of Hamburg | And 2 more authors.
Molecular Ecology | Year: 2010

Despite the advantage of avoiding the costs of sexual reproduction, asexual vertebrates are very rare and often considered evolutionarily disadvantaged when compared to sexual species. Asexual species, however, may have advantages when colonizing (new) habitats or competing with sexual counterparts. They are also evolutionary older than expected, leaving the question whether asexual vertebrates are not only rare because of their 'inferior' mode of reproduction but also because of other reasons. A paradigmatic model system is the unisexual Amazon molly, Poecilia formosa, that arose by hybridization of the Atlantic molly, Poecilia mexicana, as the maternal ancestor, and the sailfin molly, Poecilia latipinna, as the paternal ancestor. Our extensive crossing experiments failed to resynthesize asexually reproducing (gynogenetic) hybrids confirming results of previous studies. However, by producing diploid eggs, female F 1-hybrids showed apparent preadaptation to gynogenesis. In a range-wide analysis of mitochondrial sequences, we examined the origin of P. formosa. Our analyses point to very few or even a single origin(s) of its lineage, which is estimated to be approximately 120 000 years old. A monophyletic origin was supported from nuclear microsatellite data. Furthermore, a considerable degree of genetic variation, apparent by high levels of clonal microsatellite diversity, was found. Our molecular phylogenetic evidence and the failure to resynthesize the gynogenetic P. formosa together with the old age of the species indicate that some unisexual vertebrates might be rare not because they suffer the long-term consequences of clonal reproduction but because they are only very rarely formed as a result of complex genetic preconditions necessary to produce viable and fertile clonal genomes and phenotypes ('rare formation hypothesis'). © 2010 Blackwell Publishing Ltd.


Peck B.,The Institute of Cancer Research | Schulze A.,Theodor Boveri Institute | Schulze A.,Comprehensive Cancer Center Mainfranken
FEBS Journal | Year: 2016

Metabolic reprogramming is a central feature of transformed cells. Cancer metabolism is now fully back in the focus of cancer research, as the interactions between oncogenic signalling and cellular metabolic processes are uncovered. One aspect of metabolic reprogramming in cancer is alterations in lipid metabolism. In contrast to most untransformed tissues, which satisfy their demand from dietary lipids, cancer cells frequently re-activate de novo lipogenesis. However, compounds targeting fatty acid synthase (FASN), a multiprotein complex integral to lipogenesis, have so far shown limited efficacy in pre-clinical cancer models and to date only one FASN inhibitor has entered clinical trials. Recently, a number of studies have suggested that enhanced production of fatty acids in cancer cells could also increases their dependence on the activity of desaturases, a class of enzymes that insert double bonds into acyl-CoA chains. Targeting desaturase activity could provide a window of opportunity to selectively interfere with the metabolic activity of cancer cells. This review will summarise some key findings that implicate altered lipid metabolism in cancer and investigate the molecular interactions between lipid desaturation and cancer cell survival. © 2016 Federation of European Biochemical Societies


Gatto F.,Chalmers University of Technology | Schulze A.,Theodor Boveri Institute | Schulze A.,Comprehensive Cancer Center Mainfranken | Nielsen J.,Chalmers University of Technology
Cell Reports | Year: 2016

Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network. © 2016 The Author(s)


O'Meara E.,Our Ladys Childrens Hospital | Stack D.,Our Ladys Childrens Hospital | Lee C.-H.,Vancouver General Hospital | Garvin A.J.,Wake forest University | And 11 more authors.
Journal of Pathology | Year: 2012

Clear cell sarcoma of kidney (CCSK) is classified as a tumour of unfavourable histology by the National Wilms'Tumor Study Group. It has worse clinical outcomes than Wilms' tumour. Virtually nothing is known about CCSK biology, as there have been very few genetic aberrations identified to act as pointers in this cancer. Three cases of CCSK bearing a chromosomal translocation, t(10;17)(q22;p13), have been individually reported but not further investigated to date. The aim of this research was to characterize t(10;17)(q22;p13) in CCSK to identify the genes involved in the translocation breakpoints. Using fluorescently labelled bacterial artificial chromosomes (BACs) and a chromosome-walking strategy on an index case of CCSK with t(10;17)(q22;p13) by karyotype, we identified the chromosomal breakpoints on 17p13.3 and 10q22.3. The translocation results in rearrangement of YWHAE on chromosome 17 and FAM22 on chromosome 10, producing an in-frame fusion transcript of ∼3 kb, incorporating exons 1-5 of YWHAE and exons 2-7 of FAM22, as determined by RT-PCR using YWHAE- and FAM22-specific primers. The YWHAE-FAM22 transcript was detected in six of 50 further CCSKs tested, therefore showing an overall incidence of 12% in our cohort. No transcript-positive cases presented with stage I disease, despite this being the stage for 31% of our cohort. Tumour cellularity was significantly higher in the cases that were transcript-positive. Based on the chromosome 10 breakpoint identified by FISH and the sequences of the full-length transcripts obtained, the FAM22 members involved in the translocation in these CCSK cases include FAM22B and FAM22E. Elucidation of the role of YWHAE-FAM22 in CCSK will assist development of more efficient and targeted therapies for this childhood cancer, which currently has poor outcomes. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


PubMed | Cancer Research UK Research Institute and Theodor Boveri Institute
Type: Journal Article | Journal: The FEBS journal | Year: 2016

Metabolic reprogramming is a central feature of transformed cells. Cancer metabolism is now fully back in the focus of cancer research, as the interactions between oncogenic signalling and cellular metabolic processes are uncovered. One aspect of metabolic reprogramming in cancer is alterations in lipid metabolism. In contrast to most untransformed tissues, which satisfy their demand from dietary lipids, cancer cells frequently re-activate de novo lipogenesis. However, compounds targeting fatty acid synthase (FASN), a multiprotein complex integral to lipogenesis, have so far shown limited efficacy in pre-clinical cancer models and to date only one FASN inhibitor has entered clinical trials. Recently, a number of studies have suggested that enhanced production of fatty acids in cancer cells could also increases their dependence on the activity of desaturases, a class of enzymes that insert double bonds into acyl-CoA chains. Targeting desaturase activity could provide a window of opportunity to selectively interfere with the metabolic activity of cancer cells. This review will summarise some key findings that implicate altered lipid metabolism in cancer and investigate the molecular interactions between lipid desaturation and cancer cell survival.


PubMed | Theodor Boveri Institute
Type: Journal Article | Journal: Nature reviews. Cancer | Year: 2016

Lipid metabolism, in particular the synthesis of fatty acids (FAs), is an essential cellular process that converts nutrients into metabolic intermediates for membrane biosynthesis, energy storage and the generation of signalling molecules. This Review explores how different aspects of FA synthesis promote tumorigenesis and tumour progression. FA synthesis has received substantial attention as a potential target for cancer therapy, but strategies to target this process have not yet translated into clinical practice. Furthermore, efforts to target this pathway must consider the influence of the tumour microenvironment.

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