Radboud Institute for Molecular Life science

Nijmegen, Netherlands

Radboud Institute for Molecular Life science

Nijmegen, Netherlands

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Driessen B.J.H.,University Utrecht | Logie C.,Radboud Institute for Molecular Life science | Vonk L.A.,University Utrecht
Cell Biology and Toxicology | Year: 2017

The repair of articular cartilage needs a sufficient number of chondrocytes to replace the defect tissue, and therefore, expansion of cells is generally required. Chondrocytes derived by cellular reprogramming may provide a solution to the limitations of current (stem) cell-based therapies. In this article, two distinct approaches—induced pluripotent stem cell (iPSC)-mediated reprogramming and direct lineage conversion—are analysed and compared according to criteria that encompass the qualification of the method and the derived chondrocytes for the purpose of clinical application. Progress in iPSC generation has provided insights into the replacement of reprogramming factors by small molecules and chemical compounds. As follows, multistage chondrogenic differentiation methods have shown to improve the chondrocyte yield and quality. Nevertheless, the iPSC ‘detour’ remains a time- and cost-consuming approach. Direct conversion of fibroblasts into chondrocytes provides a slight advantage over these aspects compared to the iPSC detour. However, the requirement of constitutive transgene expression to inhibit hypertrophic differentiation limits this approach of being translated to the clinic. It can be concluded that the quality of the derived chondrocytes highly depends on the characteristics of the reprogramming method and that this is important to keep in mind during the experimental set-up. Further research into both reprogramming approaches for clinical cartilage repair has to include proper control groups and epigenetic profiling to optimize the techniques and eventually derive functionally stable articular chondrocytes. © 2017 The Author(s)

Bakdash G.,University of Amsterdam | Bakdash G.,Radboud Institute for Molecular Life science | Vogelpoel L.T.C.,University of Amsterdam | Van Capel T.M.M.,University of Amsterdam | And 2 more authors.
Mucosal Immunology | Year: 2015

The vitamin A metabolite all-trans retinoic acid (RA) is an important determinant of intestinal immunity. RA primes dendritic cells (DCs) to express CD103 and produce RA themselves, which induces the gut-homing receptors α4β7 and CCR9 on T cells and amplifies transforming growth factor (TGF)-β-mediated development of Foxp3 + regulatory T (Treg) cells. Here we investigated the effect of RA on human DCs and subsequent development of T cells. We report a novel role of RA in immune regulation by showing that RA-conditioned human DCs did not substantially enhance Foxp3 but induced α4β7 + CCR9 + T cells expressing high levels of interleukin (IL)-10, which were functional suppressive Treg cells. IL-10 production was dependent on DC-derived RA and was maintained when DCs were stimulated with toll-like receptor ligands. Furthermore, the presence of TGF-β during RA-DC-driven T-cell priming favored the induction of Foxp3 + Treg cells over IL-10 + Treg cells. Experiments with naive CD4 + T cells stimulated by anti-CD3 and anti-CD28 antibodies in the absence of DCs emphasized that RA induces IL-10 in face of inflammatory mediators. The data thus show for the first time that RA induces IL-10-producing Treg cells and postulates a novel mechanism for IL-10 in maintaining tolerance to the intestinal microbiome.

Bakdash G.,University of Amsterdam | Bakdash G.,Radboud Institute for Molecular Life science | van Capel T.M.M.,University of Amsterdam | Mason L.M.K.,University of Amsterdam | And 2 more authors.
Vaccine | Year: 2014

Vitamin D is recognized as a potent immunosuppressive drug. The suppressive effects of vitamin D are attributed to its physiologically active metabolite 1,25 dihydroxy vitamin D3 (calcitriol), which was shown, to prime dendritic cells (DCs) to promote the development of regulatory T (Treg) cells. Despite the potential benefit in treating autoimmune diseases, clinical application of calcitriol is hindered by deleterious side effects manifested by hypercalcemia and hypercalciuria. Conversely, the physiological precursors of calcitriol, vitamin D3 (cholecalciferol) and its first metabolite 25-hydroxy vitamin D3 (calcidiol) are widely applied in the clinic due to their low calcimic burden. However, the mechanisms by which cholecalciferol and calcidiol may modulate adaptive immunity remain elusive. This prompted us to unravel the immunosuppressive capacity of these precursors by assessing their influence on DC functions and the subsequent polarization of naïve CD4+ T cells. In this study we show that, whereas cholecalciferol has insignificant effects on DC maturation and cytokine production, it only weakly primed DCs to induce suppressive T cells. However, like calcitriol, calcidiol not only exerted an inhibitory effect on DC maturation and cytokine production, and primed DCs to promote the development of suppressive IL-10-producing Treg cells. Strikingly, in contrast to the population of IL-10-producing Treg cells induced by calcitriol-primed DCs, the IL-10-producing Treg cells induced by calcidiol-primed DCs exhibited sustained IFN-γ production in face of their suppressive capacity. Experiments with the steroid synthesis inhibitor ketoconazole indicated that the immunomodulatory features of the precursors are dependent on their conversion into calcitriol. Collectively, calcidiol is a potent immune modulator, which may be more adequate than calcitriol for the treatment of chronic inflammatory diseases, since it is less hypercalcimic. This may be of particular interest for the treatment of allergic disease, where concurrent suppression and sustained IFN-γ production by Treg cells effectively counterbalance the Th2-dominated immune responses. © 2014 Elsevier Ltd.

Haeger A.,Radboud Institute for Molecular Life science | Krause M.,Radboud Institute for Molecular Life science | Wolf K.,Radboud Institute for Molecular Life science | Friedl P.,Radboud Institute for Molecular Life science | And 2 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2014

Background Cancer invasion is a multi-step process which coordinates interactions between tumor cells with mechanotransduction towards the surrounding matrix, resulting in distinct cancer invasion strategies. Defined by context, mesenchymal tumors, including melanoma and fibrosarcoma, develop either single-cell or collective invasion modes, however, the mechanical and molecular programs underlying such plasticity of mesenchymal invasion programs remain unclear. Methods To test how tissue anatomy determines invasion mode, spheroids of MV3 melanoma and HT1080 fibrosarcoma cells were embedded into 3D collagen matrices of varying density and stiffness and analyzed for migration type and efficacy with matrix metalloproteinase (MMP)-dependent collagen degradation enabled or pharmacologically inhibited. Results With increasing collagen density and dependent on proteolytic collagen breakdown and track clearance, but independent of matrix stiffness, cells switched from single-cell to collective invasion modes. Conversion to collective invasion included gain of cell-to-cell junctions, supracellular polarization and joint guidance along migration tracks. Conclusions The density of the extracellulair matrix (ECM) determines the invasion mode of mesenchymal tumor cells. Whereas fibrillar, high porosity ECM enables single-cell dissemination, dense matrix induces cell-cell interaction, leader-follower cell behavior and collective migration as an obligate protease-dependent process. General significance These findings establish plasticity of cancer invasion programs in response to ECM porosity and confinement, thereby recapitulating invasion patterns of mesenchymal tumors in vivo. The conversion to collective invasion with increasing ECM confinement supports the concept of cell jamming as a guiding principle for melanoma and fibrosarcoma cells into dense tissue. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. © 2014 Elsevier B.V.

Bol K.F.,Radboud Institute for Molecular Life science | Bol K.F.,Radboud University Nijmegen | Schreibelt G.,Radboud Institute for Molecular Life science | Gerritsen W.R.,Radboud University Nijmegen | And 4 more authors.
Clinical Cancer Research | Year: 2016

Dendritic cell (DC) vaccination in cancer patients aims to induce or augment an effective antitumor immune response against tumor antigens and was first explored in a clinical trial in the 1990s. More than two decades later, numerous clinical trials have been performed or are ongoing with a wide variety of DC subsets, culture protocols, and treatment regimens. The safety of DC vaccination and its ability to induce antitumor responses have clearly been established; however, although scattered patients with long-term benefit were reported, DC vaccines have not yet fulfilled their promise, perhaps mainly due to the lack of large-scale well-conducted phase II/III trials. To allow meaningful multicenter phase III trials, the production of DC vaccines should be standardized between centers which is now becoming feasible. To improve the efficacy of DC-based immunotherapy, it could be combined with other treatments. © 2016 American Association for Cancer Research.

Esmaeili M.,Norwegian University of Science and Technology | Hamans B.C.,Radboud University Nijmegen | Navis A.C.,Radboud University Nijmegen | Van Horssen R.,Radboud Institute for Molecular Life science | And 6 more authors.
Cancer Research | Year: 2014

Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered phospholipid metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed 31P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation. 31P-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by 31P highresolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro 31P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-R132H mutation alters phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma. © 2014 American Association for Cancer Research.

Vallen M.J.E.,Radboud University Nijmegen | van der Steen S.C.H.A.,Radboud University Nijmegen | van Tilborg A.A.G.,Radboud University Nijmegen | Massuger L.F.A.G.,Radboud University Nijmegen | van Kuppevelt T.H.,Radboud Institute for Molecular Life science
Gynecologic Oncology | Year: 2014

Considering the high mortality of ovarian cancer, novel approaches for diagnostics and therapy are urgently needed. Cancer initiation, progression, and invasion occur in a complex and dynamic microenvironment which depends on the interplay between host cell responses and tumor activity. Chondroitin sulfate (CS), a special highly sulfated sugar, forms an important intermediate player in this respect. Depending on the (micro)structural diversity of chondroitin sulfate chains, various ligands interact with this special group of glycosaminoglycans, making it a key molecule for many physiological and pathological processes, including cancer development. This review focuses on the various functions of chondroitin sulfate in tumor growth, angiogenesis, dissemination and immunosilencing of ovarian cancer. We also shed light on possible future diagnostic and therapeutic modalities for ovarian cancer based on the large variety in chondroitin sulfate microstructure and function. It is concluded that the class of chondroitin sulfate represents an attractive target to interfere with the process of ovarian tumorigenesis. © 2014 Elsevier Inc. All rights reserved.

Vasaturo A.,Radboud Institute for Molecular Life science | Verdoes M.,Radboud Institute for Molecular Life science | de Vries J.,Radboud Institute for Molecular Life science | Torensma R.,Radboud Institute for Molecular Life science | Figdor C.G.,Radboud Institute for Molecular Life science
Immunobiology | Year: 2015

Cancer cells evolve from normal cells throughout life and are usually recognized by our immune system and destroyed, a process called immunosurveillance. Unfortunately, in some instances cancer cells paralyze our immune system, resulting in outgrowth and spreading of the tumor. Understanding the complexity of immunomodulation by tumors is important for the development of therapeutical strategies. Nowadays, various approaches have been developed to enhance anti-tumor immune responses and abrogate the immune dampening effect of the tumor and its surrounding environment, including dendritic cell-based vaccines, therapies to counteract myeloid derived suppressor cell function within the tumor and antagonists of inhibitory signaling pathways to overcome 'immune checkpoints'.The challenge is now to find the right combination of immune based therapies to fully restore immune function and provide a more efficacious and enduring anti-tumor response. © 2014 Elsevier GmbH.

Kuiper R.P.,Radboud University Nijmegen | Kuiper R.P.,Radboud Institute for Molecular Life science | Waanders E.,Radboud University Nijmegen | Waanders E.,Radboud Institute for Molecular Life science
Nature Genetics | Year: 2014

Genomic aberrations affecting genes in B cell differentiation are hallmarks of B-precursor acute lymphoblastic leukemia (ALL). A new whole-genome sequencing study of ETV6-RUNX1-positive ALL has now identified RAG-mediated recombination, which specifically targets genes and regulatory elements active during B cell differentiation, as the underlying mechanism. © 2014 Nature America, Inc.

Haeger A.,Radboud Institute for Molecular Life science | Wolf K.,Radboud Institute for Molecular Life science | Zegers M.M.,Radboud Institute for Molecular Life science | Friedl P.,Radboud Institute for Molecular Life science | Friedl P.,University of Texas M. D. Anderson Cancer Center
Trends in Cell Biology | Year: 2015

Collective cell migration results from the establishment and maintenance of collective polarization, mechanocoupling, and cytoskeletal kinetics. The guidance of collective cell migration depends on a reciprocal process between cell-intrinsic multicellular organization with leader-follower cell behavior and results in mechanosensory integration of extracellular guidance cues. Important guidance mechanisms include chemotaxis, haptotaxis, durotaxis, and strain-induced mechanosensing to move cell groups along interfaces and paths of least resistance. Additional guidance mechanisms steering cell groups during specialized conditions comprise electrotaxis and passive drift. To form higher-order cell and tissue structures during morphogenesis and cancer invasion, these guidance principles act in parallel and are integrated for collective adaptation to and shaping of varying tissue environments. We review mechanochemical and electrical inputs and multiparameter signal integration underlying collective guidance, decision making, and outcome. © 2015 Elsevier Ltd.

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