Lars Zender

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (175)

  • P Piontek · M Bitzer · L Zender · [...] · RR Plentz
    Article · Aug 2016 · Zeitschrift für Gastroenterologie
  • RM Feller · M Bitzer · L Zender · [...] · RR Plentz
    Article · Aug 2016 · Zeitschrift für Gastroenterologie
  • [Show abstract] [Hide abstract] ABSTRACT: Senescence, a persistent form of cell-cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to ‘lateral induction of senescence’ through a juxtacrine NOTCH–JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. As enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared with typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.
    Article · Aug 2016 · Nature Cell Biology
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    Full-text Article · Aug 2016 · Cancer cell
  • Article · Jul 2016 · Cancer Research
  • Dauch Daniel · Ramona Rudalska · Giacomo Cossa · [...] · Lars Zender
    Article · Jul 2016 · Cancer Research
  • [Show abstract] [Hide abstract] ABSTRACT: The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarci-nomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumori-genesis in liver cancer.
    Article · Jun 2016 · Cell
  • Daniel Dauch · Ramona Rudalska · Giacomo Cossa · [...] · Lars Zender
    [Show abstract] [Hide abstract] ABSTRACT: MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19(ARF). MYC directly binds to AURKA, and inhibition of this protein-protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs.
    Article · May 2016 · Nature Medicine
  • C. Klein · L. Zender · N.P. Malek
    [Show abstract] [Hide abstract] ABSTRACT: Background and objective The inclusion of molecular diagnostics in the clinical oncological routine and the therapeutic decision-making based on oncogenetic results necessitate a basic understanding of the molecular mechanisms of tumorigenesis. This article describes the principles of malignant transformation in a simplified form and elucidates terms such as “oncogene” and tumor-suppressor gene”. Methods A database search and evalution of the current literature were carried out. Results In carcinogenesis three forms of mutations can be differentiated, which can lead to malignant transformation of cells: mutations in oncogenes, mutations in tumor-suppressor genes and in stability genes; however, a tumor does not as a rule arise from a single mutation of a certain gene. A cell only degenerates when several genes are mutated. Oncogenes are genes which arise from proto-oncogenes by mutation and promote the transformation of a normal cell to a malignant cell, mostly by increasing the proliferation rate. Tumor-suppressor genes are mostly genes that, in a jeopardizing situation for the cell, initiate a cell cycle arrest or have proapoptotic features and should, therefore, prevent malignant degeneration; however, if such a gene mutates, exactly the opposite can occur. If the mutation reduces the activity of the gene product, this can favor the formation of a malignant tumor. The third class of mutations, which contribute to malignant degeneration can be summarized under the term stability (caretaker) gene mutations. Over the last decade cancer research has revealed that despite the multitude of proto-oncogenes, oncogenes and tumor-suppressor genes, only a manageable number of signal cascades are involved in oncogenesis. This information is of clinical relevance to the extent that in animal experiments the switching off of various genes in the same pathway led to the same phenotype and this concept can also be utilized in oncology. The cancer researchers Douglas Hanahan and Robert Weinberg have defined 10 characteristic features that every cancer cell needs in order to initiate an invasive and fatal cancerous disease (so-called hallmarks of cancer).
    Article · Jan 2016 · Der Onkologe
  • [Show abstract] [Hide abstract] ABSTRACT: Senescence, a persistent form of cell cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence (OIS) is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, whilst suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to ‘lateral induction of senescence’ through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. Because enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared to typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.
    Article · Jan 2016
  • Article · Oct 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
    Full-text Article · Aug 2015 · Nature Cell Biology
  • B Schulte · L Zender · MP Manns · [...] · F Kühnel
    Article · Aug 2015 · Zeitschrift für Gastroenterologie
  • M Waltemathe · S Hütker · L Zender · [...] · S Kubicka
    Article · Aug 2015 · Zeitschrift für Gastroenterologie
  • L Zender · M Waltemathe · S Hütker · [...] · S Kubicka
    Article · Aug 2015 · Zeitschrift für Gastroenterologie
  • Tobias Eggert · Juling Ji · Lars Zender · [...] · Tim F. Greten
    Article · Aug 2015 · Cancer Research
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    [Show abstract] [Hide abstract] ABSTRACT: Dendritic cells (DCs) are professional antigen-presenting cells playing a crucial role in the initiation of T-cell responses to combat infection. However, systemic bacterial infection with various pathogens leads to DC-depletion in humans and mice. The mechanisms of pathogen-induced DC-depletion remain poorly understood. Previously, we showed that mice infected with Yersinia enterocolitica (Ye) had impaired de novo DC-development, one reason for DC-depletion. Here, we extend these studies to gain insight into the molecular mechanisms of DC-depletion and the impact of different bacteria on DC-development. We show that the number of BM hematopoietic progenitors committed to the DC lineage is reduced following systemic infection with different Gram-positive and Gram-negative bacteria. This is associated with a TLR4- and IFN-γ-signaling dependent increase of committed monocyte progenitors in the BM and mature monocytes in the spleen upon Ye-infection. Adoptive transfer experiments revealed that infection-induced monopoiesis occurs at the expense of DC-development. Our data provide evidence for a general response of hematopoietic progenitors upon systemic bacterial infections to enhance monocyte production, thereby increasing the availability of innate immune cells for pathogen control, whereas impaired DC-development leads to DC-depletion, possibly driving transient immunosuppression in bacterial sepsis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text Article · Jul 2015 · European Journal of Immunology
  • Lars Zender · Michael Hemann
    [Show abstract] [Hide abstract] ABSTRACT: Hepatic progenitor cells isolated from fetal liver can be transplanted into recipient mice to reconstitute an organ system. Retroviral infection can be used to introduce putative oncogenes or short-hairpin RNAs (shRNAs) targeting putative tumor suppressors into the cells; reconstituted mice then develop livers that are chimeric for cells bearing a specific alteration. This approach has the advantage of examining tumorigenesis on a largely wild-type background (if only a subset of cells are infected), a situation that more accurately parallels the human situation. Additionally, tumor development occurs within the appropriate native microenvironment. Here, we describe the isolation of hepatic progenitor cells, as well as the reconstitution and tumor monitoring of recipient mice. © 2015 Cold Spring Harbor Laboratory Press.
    Article · Jul 2015 · Cold Spring Harbor Protocols
  • M. Hoare · Y. Ito · T.-W. Kang · [...] · M. Narita
    [Show abstract] [Hide abstract] ABSTRACT: Introduction Oncogene-induced senescence (OIS) is an intrinsic tumour suppressor mechanism, but its impact on tumorigenesis is largely dependent on the nature of SASP, senescence-associated secretory phenotype. Major components of the SASP include TGFβ1 and pro-inflammatory cytokines, such as IL1A, IL6, and IL8 that have pleiotropic context-dependent effects. Method We utilised the well validated ER:RasG12VIMR90 HDF in vitromodel which undergo Ras-induced senescence (RIS) with 4OHT. In vivohepatocyte RIS was achieved with hydrodynamic tail-vein injection of NRasG12V-containing transposons. Results Previously, we have shown that Notch1, a highly conserved receptor is up-regulated in RIS. In contrast to the up-regulation of Notch1, downstream signalling is dynamically regulated; Notch-target genes were transiently up-regulated at an early phase of RIS, but down-regulated at full senescence. The dynamic expression pattern of N1ICD and TGF-β1 expression were nearly identical, and inversely correlated with the cytokines, IL1A and IL8. Inhibition of Notch1 signalling, through expression of a dominant-negative form of the Notch1 binding partner MAML1, led to a reduction in TGF-β1, but increased IL1A and IL8 expression during RIS, suggesting Notch1 signalling plays a critical role in secretome switching. It has been shown that the SASP in RIS is regulated by two major transcription factors, NFkB and CEBPβ. Strikingly, over-expression of N1ICD strongly down-regulated CEBPβ, but not NFkB, in fully established RIS cells. Further, expression of ectopic CEBPβ in N1ICD-expressing cells partially restored levels of IL6/8. N1ICD was also able to suppress pro-inflammatory cytokine expression in TNF-α stimulated cells, through repression of CEBPβ. These data indicate that Notch1 represses pro-inflammatory cytokines by down-regulating CEBPβ. Finally, Notch1 up-regulation in OIS was confirmed in Nras-driven hepatocyte senescence; Notch1 inhibition through dnMAML1 promoted immune-mediated clearance of senescent hepatocytes. Conclusion We propose that the transition to OIS is correlated with a switch from Notch1-driven TGFβ-rich secretome to a CEBPβ-driven IL1/8 rich secretome, and that dynamic Notch1 signalling modulates senescence and its long-term fate strictly through a non-cell-autonomous fashion. Disclosure of interest None Declared.
    Article · Apr 2015 · Journal of Hepatology
  • Article · Apr 2015 · Journal of Hepatology

Publication Stats

9k Citations

Institutions

  • 2015
    • University of Tuebingen
      • Department of Internal Medicine
      Tübingen, Baden-Württemberg, Germany
  • 2011
    • Helmholtz Centre for Infection Research
      Brunswyck, Lower Saxony, Germany
  • 2007
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2000
    • Hochschule Hannover
      Hanover, Lower Saxony, Germany