Comprehensive Cancer Center Mainfranken

Würzburg, Germany

Comprehensive Cancer Center Mainfranken

Würzburg, Germany
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Sander B.,University of Würzburg | Xu W.,Comprehensive Cancer Center Mainfranken | Xu W.,University of Würzburg | Eilers M.,Comprehensive Cancer Center Mainfranken | And 4 more authors.
eLife | Year: 2017

The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues—a mechanism that may be exploited for cancer therapy. © Sander et al.

Schug Z.T.,Cancer Research UK Research Institute | Peck B.,Cancer Research UK Research Institute | Peck B.,The Institute of Cancer Research | Jones D.T.,Weatherall Institute of Molecular Medicine | And 32 more authors.
Cancer Cell | Year: 2015

A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment. © 2015 The Authors.

Rasche L.,University of Würzburg | Duell J.,University of Würzburg | Morgner C.,University of Würzburg | Chatterjee M.,Comprehensive Cancer Center Mainfranken | And 5 more authors.
PLoS ONE | Year: 2013

In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM. © 2013 Rasche et al.

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)

Wolf E.,University of Würzburg | Gebhardt A.,University of Würzburg | Kawauchi D.,St Jude Childrens Research Hospital | Walz S.,University of Würzburg | And 8 more authors.
Nature Communications | Year: 2013

Miz1 is a zinc finger protein that regulates the expression of cell cycle inhibitors as part of a complex with Myc. Cell cycle-independent functions of Miz1 are poorly understood. Here we use a Nestin-Cre transgene to delete an essential domain of Miz1 in the central nervous system (Miz1 ΔPOZNes). Miz1 ΔPOZNes mice display cerebellar neurodegeneration characterized by the progressive loss of Purkinje cells. Chromatin immunoprecipitation sequencing and biochemical analyses show that Miz1 activates transcription upon binding to a non-palindromic sequence present in core promoters. Target genes of Miz1 encode regulators of autophagy and proteins involved in vesicular transport that are required for autophagy. Miz1 ΔPOZ neuronal progenitors and fibroblasts show reduced autophagic flux. Consistently, polyubiquitinated proteins and p62/Sqtm1 accumulate in the cerebella of Miz1 ΔPOZNes mice, characteristic features of defective autophagy. Our data suggest that Miz1 may link cell growth and ribosome biogenesis to the transcriptional regulation of vesicular transport and autophagy. © 2013 Macmillan Publishers Limited. All rights reserved.

Verburg F.A.,University of Würzburg | Verburg F.A.,RWTH Aachen | Mader U.,Comprehensive Cancer Center Mainfranken | Tanase K.,University of Würzburg | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Objective: Differentiated thyroid carcinoma (DTC) generally has agoodprognosis. As yet, however, it is unclear whether life expectancy is reduced in these patients and, if so, to what extent. The aim of this study was to determine how the all-cause mortality rate in DTC patients compares to that of the general population. Design: A prospective database study was conducted. Patients: The study included 2011DTCpatients treated in our hospital from 1980-2011. All patients received total thyroidectomy with subsequent 131I ablation, except for those with an isolated papillary microcarcinoma. Survival data for the general German population were obtained from the German Federal Statistics Agency and matched to our DTC population for age and sex. Results: Patients who were at least 45 yr old at diagnosis and had extensive perithyroidal invasion (UICC/AJCC TNM system, 7th edition, stages IVa and IVb), lateral cervical lymph node metastases (TNM stage IVa), or distant metastases (TNM stage IVc) showed a clearly reduced life expectancy [relative cumulative survival rate (observed:expected) for stage IVc after 20 yr, 0.295; 95% confidence interval, 0.033-0.556]. In patients over 60 yr of age at diagnosis, the loss of life expectancy was (much) greater than for those aged 45-59 yr in all groups. Life expectancy was not reduced in patients with TNM stages I, II, or III (86% of patients). Conclusion: Life expectancy is not significantly reduced in 86% of DTC patients; only patients at least 45 yr old with extensive local invasion, lateral lymph node metastases, and/or distant metastases (TNM stages IVa, IVb, and IVc) at diagnosis showed a clearly lower life expectancy. Copyright © 2013 by The Endocrine Society.

Kunzmann V.,Comprehensive Cancer Center Mainfranken | Kunzmann V.,The Interdisciplinary Center | Smetak M.,Institute of Medical Oncology and Hematology | Kimmel B.,Comprehensive Cancer Center Mainfranken | And 7 more authors.
Journal of Immunotherapy | Year: 2012

Emerging evidence suggests that nitrogen-containing bisphosphonates have direct and indirect anticancer effects including immunomodulatory effects. Using in vivo targeting of bisphosphonate-reactive γδ T cells by adding low-dose interleukin-2 to zoledronic acid, we evaluated the safety, pharmacodynamics, and antitumor activity of this immunotherapy approach in 21 adults with advanced malignancies (renal cell carcinoma [RCC], malignant melanoma, and acute myeloid leukemia). A total of 58 treatment cycles were administered and the median number of treatment cycles was 2.7 (range, 1 to 6). The regimen was well tolerated, with no grade 3 to 4 drug-related adverse events, except for fever. No objective responses were observed in both cohorts of solid tumors (RCC and malignant melanoma), whereas 2 patients with acute myeloid leukemia (25%) achieved objective tumor responses (partial remission). Pharmacodynamic analyses showed significant in vivo activation (interferon-γ production) and expansion of γδ T cells in all evaluable patients. High pretreatment serum vascular endothelial growth factor (VEGF) levels and an unexpected increase in VEGF induced by zoledronic acid plus low-dose interleukin-2 were correlated with the lack of a clinical response. In conclusion, this study indicates that immunotherapy-induced VEGF can limit clinical innate tumor immune responses, especially for angiogenesis-dependent solid tumors. Our data challenge the current cellular immunotherapy paradigms in the treatment of cancer. Copyright © 2012 by Lippincott Williams & Wilkins.

Rasche L.,University of Würzburg | Bernard C.,University of Würzburg | Topp M.S.,University of Würzburg | Kapp M.,University of Würzburg | And 6 more authors.
Annals of Hematology | Year: 2012

Extramedullary (e) relapse in multiple myeloma (MM) has an adverse prognosis, but knowledge concerning biological features and preferred treatment is scarce. We screened the myeloma registry of our institution for eMM relapses and identified 24 cases among 357 patients (pts). Only 8% of eMM relapses occurred after initial therapy, but 54% occurred after third-line or subsequent therapy. Baseline molecular cytogenetics revealed high-risk features in 10 of 19 evaluable patients. Most frequently, eMM presented as soft tissue (67%) and organ involvement (25%) or malignant effusion (12.5%). Incidence of leptomeningeal/CNS involvement was 21%. At eMM relapse, bone marrow infiltration was absent in 46% and low in 21%. Ten eMM biopsies were available showing increased proliferation, i.e., Ki-67 of 67% (range, 30-90%) of all cancer cells. Pts received radiation therapy, dose-intense chemotherapy, novel agents, and allogeneic SCT resulting in an overall response rate of 54%. Median progression-free survival was 2 (95% CI 0.08-3.92) and median overall survival 7 months (95% CI 3.56-10.43), respectively, with only three patients being alive at 12 months from diagnosis. EMM relapse may present at any anatomical site with frequent CNS involvement. Biological features include increased proliferation and low rate of marrow involvement. Prognosis remains poor despite intensive treatment. © 2012 Springer-Verlag.

Rauert H.,University of Würzburg | Stuhmer T.,Comprehensive Cancer Center Mainfranken | Bargou R.,Comprehensive Cancer Center Mainfranken | Wajant H.,University of Würzburg | Siegmund D.,University of Würzburg
Cell Death and Disease | Year: 2011

The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFκB-mediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFκB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival. © 2011 Macmillan Publishers Limited.

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