Ville Rantanen

University of Helsinki, Helsinki, Uusimaa, Finland

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Publications (31)176.48 Total impact

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    ABSTRACT: Lymphatic invasion and accumulation of continuous collagen bundles around tumor cells are associated with poor melanoma prognosis, but the underlying mechanisms and molecular determinants have remained unclear. We show here that a copy number gain or overexpression of the membrane-type matrix metalloproteinase MMP16 is associated with poor clinical outcome, collagen bundle assembly around tumor cell nests, and lymphatic invasion. In cultured WM852 melanoma cells derived from human melanoma metastasis, silencing of MMP16 resulted in cell-surface accumulation of the MMP16 substrate MMP14 as well as L1CAM cell adhesion molecule, identified here as a novel MMP16 substrate. When limiting the activities of these transmembrane protein-substrates towards pericellular collagen degradation, cell junction disassembly, and blood endothelial transmigration, MMP16 supported nodular-type growth of adhesive collagen-surrounded melanoma cell nests, coincidentally steering cell collectives into lymphatic vessels. These results uncover a novel mechanism in melanoma pathogenesis, whereby restricted collagen infiltration and limited mesenchymal invasion are unexpectedly associated with the properties of the most aggressive tumors, revealing MMP16 as a putative indicator of adverse melanoma prognosis. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 03/2015; 75(10). DOI:10.1158/0008-5472.CAN-14-1923 · 9.28 Impact Factor
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    ABSTRACT: Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRγ, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXRγ-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.
    Cell Reports 10/2014; 9(2). DOI:10.1016/j.celrep.2014.09.001 · 8.36 Impact Factor
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    ABSTRACT: The gelatinase enzymes, matrix metalloproteinases -2 and -9, are central mediators of blood–brain barrier disruption, actively studied in experimental models of neurological disease. Staining with in situ zymography (ISZ) allows visualization of gelatinase activity directly in brain tissue sections. However, quantifying microvascular gelatinase activity from ISZ-images is challenging and time consuming, as surrounding cell types often show significant confounding activity. We describe validation and performance of a workflow for automated image analysis of cerebromicrovascular gelatinase activity, now released for open-access use. In comparison to manual analysis, the automated workflow showed superior accuracy, was faster to execute and allows for more detailed analysis of heterogeneity in the microvasculature. We further suggest recommendations for quantifying and reporting this type of activity in experimental studies, focusing on ischemic stroke.
    Microvascular Research 09/2014; 97. DOI:10.1016/j.mvr.2014.08.009 · 2.43 Impact Factor
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    Ville Rantanen · Miko Valori · Sampsa Hautaniemi
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    ABSTRACT: Modern microscopes produce vast amounts of image data, and computational methods are needed to analyze and interpret these data. Furthermore, a single image analysis project may require tens or hundreds of analysis steps starting from data import and pre-processing to segmentation and statistical analysis; and ending with visualization and reporting. To manage such large-scale image data analysis projects, we present here a modular workflow system called Anima. Anima is designed for comprehensive and efficient image data analysis development, and it contains several features that are crucial in high-throughput image data analysis: programing language independence, batch processing, easily customized data processing, interoperability with other software via application programing interfaces, and advanced multivariate statistical analysis. The utility of Anima is shown with two case studies focusing on testing different algorithms developed in different imaging platforms and an automated prediction of alive/dead C. elegans worms by integrating several analysis environments. Anima is a fully open source and available with documentation at www.anduril.org/anima.
    Frontiers in Bioengineering and Biotechnology 07/2014; 2:25. DOI:10.3389/fbioe.2014.00025
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    ABSTRACT: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL. We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients. We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis. COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL. ClinicalTrials.gov NCT01502982.
    PLoS ONE 03/2014; 9(3):e91031. DOI:10.1371/journal.pone.0091031 · 3.23 Impact Factor
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    ABSTRACT: Oral immunotherapy (OIT) with cow's milk (CM) has been reported to induce a number of specific antibody responses, but these remain to be fully characterized. Our objective was to explore whether IgE and IgG4 epitope binding profiles could predict the risk of side effects during CM OIT. The study population consisted of 32 children (6-17 yr of age) with CM allergy: 26 children who successfully completed OIT and six children who discontinued therapy due to adverse reactions. We investigated sera drawn before and after OIT. We analyzed specific IgE and IgG4 binding to CM protein-derived peptides with a microarray-based immunoassay. Antibody binding affinity was analyzed with a competition assay where CM proteins in solution competed with peptides printed on the microarray. IgE binding to CM peptides decreased and IgG4 binding increased following the OIT in children who attained desensitization. Compared with children who successfully completed OIT, those who discontinued OIT due to adverse reactions developed increased quantities and affinity of epitope-specific IgE antibodies and a broader diversity of IgE and IgG4 binding, but less overlap in IgE and IgG4 binding to CM peptides. Detailed analysis of IgE and IgG4 binding to CM peptides may help in predicting whether CM OIT will be tolerated successfully. It may thus improve the safety of the therapy.
    Pediatric Allergy and Immunology 01/2014; 25(3). DOI:10.1111/pai.12186 · 3.86 Impact Factor
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    ABSTRACT: Thrombolysis with tissue plasminogen activator (tPA) traditionally demands baseline imaging to rule out intracerebral hemorrhage (ICH), which causes delays in treatment. Preventing possible adverse effects of tPA on ICH would allow rapid on-site thrombolysis in patients with presumed acute ischemic stroke, reducing onset-to-treatment times. We examined how intravenous tPA alters ICH evolution during an extended follow-up, and how mast cell stabilization affects this process. Intracerebral hemorrhage was induced in rats by collagenase injection. Rats received either saline (n=10), tPA (n=13), tPA+low-dose cromoglycate (n=10), or tPA+high-dose cromoglycate (n=10). Magnetic resonance imaging was performed at 24, 48, and 72 hours after ICH induction, together with neurologic evaluations. During 72 hours of follow-up, tPA administration did not significantly increase hematoma volume (mean±s.d. 83.5±14.3 versus 66.7±14.7 μL; P=0.256) or hemispheric expansion (14.5±5.0 versus 11.5±5.0%; P=0.457) compared with saline. However, tPA-treated animals had worse neurologic outcomes (P<0.05), and mortality (8/13 versus 3/10). Combining tPA with high-dose cromoglycate mitigated hemispheric expansion (7.4±1.7 versus 14.5±5.0%; P=0.01), improved neurologic outcome (P<0.001) and decreased mortality (1/10; P<0.05) compared with tPA alone. Our results suggest tPA increases neurologic deficit in ICH, an effect that was abolished by concomitant mast cell stabilization. Further studies are needed to establish the clinical relevance of these findings.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 October 2013; doi:10.1038/jcbfm.2013.189.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 10/2013; 34(1). DOI:10.1038/jcbfm.2013.189 · 5.34 Impact Factor
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    ABSTRACT: Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-κB signaling (P<0.005). Of the ten most up-regulated genes, expression of STX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.
    PLoS ONE 10/2013; 8(10):e77184. DOI:10.1371/journal.pone.0077184 · 3.23 Impact Factor
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    ABSTRACT: DNA damage responses (DDR) are relevant to initiation, progression and treatment of prostate cancer. Few models of the normal and malignant human prostate that maintain stromal-epithelial interactions in vivo exist to study DDR. We evaluated the feasibility of maintaining tissue slice grafts (TSGs) at subcutaneous versus subrenal capsular sites in RAG2(-/-)γC(-/-) mice to study DDR of normal and malignant glands. Take rate and histology of TSGs from fresh, precision-cut surgical specimens, maintained for 1-4 weeks in subcutaneous versus subrenal capsular sites, were compared. Induction of γH2AX, p53, ATM and apoptosis were evaluated as measures of DDR after irradiation (IR). The take rate of subcutaneous TSGs was higher than typically reported, albeit lower than at the subrenal capsular site. Subcutaneous TSGs frequently developed basal cell hyperplasia, squamous metaplasia and cystic atrophy, and cancer did not survive. In contrast, normal and malignant histology were well-maintained in subrenal capsular TSGs. Regardless of implantation site, induction of γH2AX and ATM occurred in epithelia of TSGs 1 hour post-IR and declined to basal level by 24 hours, indicating recognition and repair of DNA damage. As observed previously in prostatic ex vivo models, p53 was not activated. Notably, tumor but not normal cells responded to IR by undergoing apoptosis. To our knowledge, this is the first study of DDR in a patient-derived prostate tissue graft model. The subrenal capsular site of RAG2(-/-)γC(-/-) mice optimally maintains normal and malignant histology and function, permitting novel studies of DDR in a physiologic context.
    The Journal of urology 09/2013; 191(3). DOI:10.1016/j.juro.2013.09.007 · 3.75 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):626-626. DOI:10.1158/1538-7445.AM2013-626 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):3156-3156. DOI:10.1158/1538-7445.AM2013-3156 · 9.28 Impact Factor
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    ABSTRACT: The functionalization of natural fibers is an important task that has recently received considerable attention. We investigated the formation of a hydrophobic layer from amphiphilic diblock copolymer micelles [polystyrene-block-poly(N-methyl-4-vinyl pyridinium iodide)] on natural fibers and on a model surface (mica). A series of micelles were prepared. The micelles were characterized by using cryoscopic TEM and light scattering, and their hydrophobization capability was studied through contact angle measurements, water adsorption, and Raman imaging. Mild heat treatment (130 °C) was used to increase the hydrophobization capability of the micelles. The results showed that the micelles could not hydrophobize a model surface, but could render the natural fibers water repellent both with and without heat treatment. This effect was systematically studied by varying the composition of the constituent blocks. The results showed that the micelle size (and the molecular weight of the constituent diblock copolymers) was the most important parameter, whereas the cationic (hydrophilic) part played only a minor role. We hypothesized that the hydrophobization effect could be attributed to a combination of the micelle size and the shrinkage of the natural fibers upon drying. The shrinking caused the roughness to increase on the fiber surface, which resulted in a rearrangement of the self- assembled layer in the wet state. Consequently, the fibers became hydrophobic through the roughness effects at multiple length scales. Mild heat treatment melted the micelle core and decreased the minimum size necessary for hydrophobization.
    ChemSusChem 07/2013; 6(7). DOI:10.1002/cssc.201300218 · 7.66 Impact Factor
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    ABSTRACT: The proteasome plays an important role in proteostasis by carrying out controlled protein degradation in the cell. Impairments in proteasome function are associated with severe and often age-related diseases. Here, we have characterized a molecular mechanism linking insulin/IGF-1 signaling (IIS) to proteasome activity. We show that decreased IIS, which promotes proteostasis and longevity, increases proteasome activity through the FOXO transcription factor DAF-16 in C. elegans. Furthermore, we reveal that DAF-16 represses expression of the proteasome-associated deubiquitinating enzyme ubh-4, which we suggest functions as a tissue-specific proteasome inhibitor. Finally, we demonstrate that proteasome activation through downregulation of the ubh-4 human ortholog uchl5 increases degradation of proteotoxic proteins in mammalian cells. In conclusion, we have established a mechanism by which the evolutionarily conserved IIS contributes to the regulation of proteasome activity in a multicellular organism.
    Cell Reports 06/2013; 3(6). DOI:10.1016/j.celrep.2013.05.012 · 8.36 Impact Factor
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    ABSTRACT: Microsatellite instability can be found in approximately 15% of all colorectal cancers. To detect new oncogenes we sequenced the exomes of 25 colorectal tumors and respective healthy colon tissue. Potential mutation hot spots were confirmed in 15 genes; ADAR, DCAF12L2, GLT1D1, ITGA7, MAP1B, MRGPRX4, PSRC1, RANBP2, RPS6KL1, SNCAIP, TCEAL6, TUBB6, WBP5, VEGFB, and ZBTB2; these were validated in 86 tumors with microsatellite instability. ZBTB2, RANBP2, and PSRC1 also were found to contain hot spot mutations in the validation set. The form of ZBTB2 associated with colorectal cancer increased cell proliferation. The mutation hot spots might be used to develop personalized tumor profiling and therapy.
    Gastroenterology 05/2013; 145(3). DOI:10.1053/j.gastro.2013.05.015 · 13.93 Impact Factor
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    ABSTRACT: Glioblastoma multiforme is an aggressively invading human brain cancer, which lacks effective treatment. Axonal guidance protein, netrin-1, is overexpressed in glioblastoma tumor biopsies. By experimental overexpression we observed that netrin-1 increased and downregulation of it decreased cell invasiveness in Matrigel invasion assays. Using tandem affinity purification and mass spectrometry protein identification we observed that netrin-1 forms a complex with both Notch2 and Jagged1. Recombinant Netrin-1 colocalized with Jagged1 and Notch2 at the cell surface and was further found in the intracellular vesicles with Jagged1, but not with Notch2. Netrin-1 activated Notch signaling and subsequent glioblastoma cell invasion. Interestingly, the recombinant central domain of netrin-1 counteracted the effects of the full-length netrin-1: it inhibited glioblastoma cell invasion and Notch activation by retaining the Notch signaling complex at the cell surface. This finding may have therapeutic implications. Current results reveal a new mechanism leading to glioblastoma cell invasion, where netrin-1 activates Notch signaling.
    Journal of Cell Science 04/2013; 126(11). DOI:10.1242/jcs.120022 · 5.33 Impact Factor
  • Biophysical Journal 01/2013; 104(2):342-. DOI:10.1016/j.bpj.2012.11.1900 · 3.97 Impact Factor
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    ABSTRACT: Prostate and seminal vesicle are two similar hormone responsive human organs that differ dramatically in their cancer incidence. DNA damage response (DDR) is required for maintenance of genomic integrity. In this study we investigated the DDR and cell cycle checkpoint activation of these organs using orthotopic cultures of human surgery-derived tissues and primary cultures of isolated prostate and seminal vesicle cells. We find that the activation of ATM signaling pathway by ionizing radiation (IR) was comparable in both tissues. Previously, we have shown that the prostate secretory cells express low levels of histone variant H2AX and phosphorylated H2AX (γH2AX) after IR. Here we demonstrate that H2AX levels are low also in the secretory seminal vesicle cells suggesting that this is a common phenotype of postmitotic cells. We consequently established primary epithelial cell cultures from both organs to compare their DDR. Interestingly, contrary to human prostate epithelial cells (HPEC), primary seminal vesicle epithelial cells (HSVEC) displayed effective cell cycle checkpoints after IR and expressed higher levels of Wee1A checkpoint kinase. Furthermore, HSVEC but not HPEC cells were able to activate p53 and to induce p21 cell cycle inhibitor. Our results show that during replication, the checkpoint enforcement is more proficient in the seminal vesicle than in the prostate epithelium cells. This indicates a more stringent enforcement of DDR in replicating seminal vesicle epithelial cells, and suggests that epithelial regeneration combined with sub-optimal checkpoint responses may contribute to high frequency of genetic lesions in the prostate epithelium.
    The Prostate 07/2012; 72(10):1060-70. DOI:10.1002/pros.21509 · 3.57 Impact Factor
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    ABSTRACT: Tyrosine kinase inhibitors (TKIs) have dramatically improved treatment outcomes in chronic myeloid leukemia (CML), but a proportion of patients fail to achieve optimal molecular response. By using a phosphoproteomic approach, we aimed to discover aberrant signaling pathways and putative biomarkers in bone marrow samples of suboptimally responding patients, which could be used to guide treatment selection at the diagnosis. The study consisted of 20 chronic-phase CML patients (10 optimal and 10 suboptimal response patients based on 18 months European-Leukemia-Net criteria) and healthy bone marrow cells, and CML cell lines were used as controls. The phosphorylation profile of normal bone marrow cells diverged from CML patients expectedly but, interestingly, CML cell lines (such as K562) also showed marked difference with primary CML cells. Several phosphoproteins were elevated in suboptimal patients compared to optimal response group. Most prominent differences were seen in signal transducers and activators of transcription 5b, phospholipase C γ-1, proline-rich tyrosine kinase 2, Hck, and Paxillin. These phosphoproteins were also increased in three additional nonresponder patients studied, but each of them also had unique phosphorylation patterns, such as highly active HSP27 protein in one patient. In conclusion, suboptimal imatinib response is related to increased phosphorylation of several proteins at diagnosis, which might guide the selection of TKI therapy. Furthermore, the activation of additional BCR-ABL-independent pathways in nonresponder patients (such as the anti-apoptotic HSP27 pathway) may reveal novel therapy targets.
    Experimental hematology 05/2012; 40(9):705-714.e3. DOI:10.1016/j.exphem.2012.05.010 · 2.81 Impact Factor
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    ABSTRACT: Protein localization in dendritic spines is the focus of intense investigations within neuroscience. Applications of super-resolution microscopy to dissect nanoscale protein distributions, as shown in this work with dual-color STED, generate spatial correlation coefficients having quite small values. This means that colocalization analysis to some extent looses part of its correlative impact. In this study we thus introduced nearest neighbor analysis to quantify the spatial relations between two important proteins in neurons, the dopamine D1 receptor and Na(+),K(+)-ATPase. The analysis gave new information on how dense the D1 receptor and Na(+),K(+)-ATPase constituting nanoclusters are located both with respect to the homogenous (self to same) and the heterogeneous (same to other) topology. The STED dissected nanoscale topologies provide evidence for both a joint as well as a separated confinement of the D1 receptor and the Na(+),K(+)-ATPase in the postsynaptic areas of dendritic spines. This confined topology may have implications for generation of local sodium gradients and for structural and functional interactions modulating slow synaptic transmission processes.
    Microscopy Research and Technique 02/2012; 75(2):220-8. DOI:10.1002/jemt.21046 · 1.17 Impact Factor
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    ABSTRACT: Kaposi sarcoma (KS), an angioproliferative disease associated with Kaposi sarcoma herpesvirus (KSHV) infection, harbors a diversity of cell types ranging from endothelial to mesenchymal cells of unclear origin. We developed a three-dimensional cell model for KSHV infection and used it to demonstrate that KSHV induces transcriptional reprogramming of lymphatic endothelial cells to mesenchymal cells via endothelial-to-mesenchymal transition (EndMT). KSHV-induced EndMT was initiated by the viral proteins vFLIP and vGPCR through Notch pathway activation, leading to gain of membrane-type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive properties and concomitant changes in viral gene expression. Mesenchymal markers and MT1-MMP were found codistributed with a KSHV marker in the same cells from primary KS biopsies. Our data explain the heterogeneity of cell types within KS lesions and suggest that KSHV-induced EndMT may contribute to KS development by giving rise to infected, invasive cells while providing the virus a permissive cellular microenvironment for efficient spread.
    Cell host & microbe 12/2011; 10(6):577-90. DOI:10.1016/j.chom.2011.10.011 · 12.19 Impact Factor