Publications by authors named "Steffen Fuchs"

9 Publications

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Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma.

Nat Genet 2020 01 16;52(1):29-34. Epub 2019 Dec 16.

Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.
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http://dx.doi.org/10.1038/s41588-019-0547-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008131PMC
January 2020

Non-Coding RNA Networks in ALK-Positive Anaplastic-Large Cell Lymphoma.

Int J Mol Sci 2019 Apr 30;20(9). Epub 2019 Apr 30.

Inserm, UMR1037 CRCT, F-31000 Toulouse, France.

Non-coding RNAs (ncRNAs) are essential regulators of gene expression. In recent years, it has become more and more evident that the different classes of ncRNAs, such as micro RNAs, long non-coding RNAs and circular RNAs are organized in tightly controlled networks. It has been suggested that deregulation of these networks can lead to disease. Several studies show a contribution of these so-called competing-endogenous RNA networks in various cancer entities. In this review, we highlight the involvement of ncRNA networks in anaplastic-large cell lymphoma (ALCL), a T-cell neoplasia. A majority of ALCL cases harbor the molecular hallmark of this disease, a fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin (NPM, NPM1) gene leading to a permanently active kinase that promotes the malignant phenotype. We have focused especially on ncRNAs that are regulated by the - fusion gene and illustrate how their deregulation contributes to the pathogenesis of ALCL. Lastly, we summarize the findings and point out potential therapeutic implications.
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http://dx.doi.org/10.3390/ijms20092150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539248PMC
April 2019

Circular RNAs: a new class of biomarkers as a rising interest in laboratory medicine.

Clin Chem Lab Med 2018 11;56(12):1992-2003

Department of Urology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Circular RNAs (circRNAs) are a distinct family of RNAs derived from the non-regular process of alternative splicing. CircRNAs have recently gained interest in transcriptome research due to their potential regulatory functions during gene expression. CircRNAs can act as microRNA sponges and affect transcription through their complex involvement in regular transcriptional processes. Some early studies also suggested significant roles for circRNAs in human diseases, especially cancer, as biomarkers and potential clinical targets. Therefore, there is a great need for laboratory scientists to translate these findings into clinical tools to advance testing for human diseases. To facilitate a better understanding of the promise of circRNAs, we focus this review on selected basic aspects of circRNA research, specifically biogenesis, function, analytical issues regarding identification and validation and examples of expression data in relation to human diseases. We further emphasize the unique challenges facing laboratory medicine with regard to circRNA research, particularly in the development of robust assays for circRNA detection in different body fluids and the need to collaborate with clinicians in the design of clinical studies.
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http://dx.doi.org/10.1515/cclm-2018-0231DOI Listing
November 2018

MicroRNA-193b-3p represses neuroblastoma cell growth via downregulation of , and .

Oncotarget 2018 Apr 6;9(26):18160-18179. Epub 2018 Apr 6.

Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, Tromsø NO-9037, Norway.

Neuroblastoma is the most common diagnosed tumor in infants and the second most common extracranial tumor of childhood. The survival rate of patients with high-risk neuroblastoma is still very low despite intensive multimodal treatments. Therefore, new treatment strategies are needed. In recent years, miRNA-based anticancer therapy has received growing attention. Advances in this novel treatment strategy strongly depends on the identification of candidate miRNAs with broad-spectrum antitumor activity. Here, we identify miR-193b as a miRNA with tumor suppressive properties. We show that miR-193b is expressed at low levels in neuroblastoma cell lines and primary tumor samples. Introduction of miR-193b mimics into nine neuroblastoma cell lines with distinct genetic characteristics significantly reduces cell growth independent of risk factors such as p53 functionality or amplification. Functionally, miR-193b induces a G1 cell cycle arrest and cell death in neuroblastoma cell lines by reducing the expression of , and , three important oncogenes in neuroblastoma of which inhibition has shown promising results in preclinical testing. Therefore, we suggest that miR-193b may represent a new candidate for miRNA-based anticancer therapy in neuroblastoma.
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http://dx.doi.org/10.18632/oncotarget.24793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915064PMC
April 2018

Epigenetic silencing of miR-520c leads to induced S100A4 expression and its mediated colorectal cancer progression.

Oncotarget 2017 Mar;8(13):21081-21094

Experimental and Clinical Research Center, Charité University Medicine Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

The S100 calcium-binding protein A4 (S100A4) induces epithelial mesenchymal transition, migration, invasion, angiogenesis and metastasis. Its induced expression in several cancer types correlates with poor prognosis. Apart from the functional and transcriptional regulatory aspects of S100A4, its post-transcriptional regulation is not yet clearly elucidated. In this study, we show that microRNAs (miR) miR-505-5p and miR-520c-3p target the 3'-UTR of S100A4 and inhibits its expression and its mediated migration and invasion. 5-Aza treatment significantly increased miR-520c-3p expression and reduced the S100A4 protein amounts. The upstream promoter region of miR-520c is hypermethylated irrespective of the metastasis status of colorectal cancer (CRC) patient tissues and in all analyzed CRC cell lines. Moreover, in a cohort of CRC patient specimen (n = 59), miR-520c-3p was significantly downregulated. miR-520c-3p stably expressing HCT116 cells showed a reduced metastasis formation in livers after implanting in mice spleen. Taken together, our findings demonstrate that S100A4 is post-transcriptionally regulated by tumor suppressor miRs, miR-505c-5p and miR-520c-3p, and particularly miR-520c-3p expression is epigenetically silenced in CRC.
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http://dx.doi.org/10.18632/oncotarget.15499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400567PMC
March 2017

MACC1 is post-transcriptionally regulated by miR-218 in colorectal cancer.

Oncotarget 2016 Aug;7(33):53443-53458

Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

Metastasis is a multistep molecular network process, which is lethal for more than 90% of the cancer patients. Understanding the regulatory functions of metastasis-inducing molecules is in high demand for improved therapeutic cancer approaches. Thus, we studied the post-transcriptional regulation of the crucial carcinogenic and metastasis-mediating molecule metastasis associated in colon cancer 1 (MACC1). In silico analysis revealed MACC1 as a potential target of miR-218, a tumor suppressor miRNA. Expression of these two molecules inversely correlated in colorectal cancer (CRC) cell lines. In a cohort of CRC patient tissues (n = 59), miR-218 is significantly downregulated and MACC1 is upregulated compared with normal mucosa. Luciferase reporter assays with a construct of the MACC1-3'-UTR harboring either the wild type or the mutated miR-218 seed sequence confirmed the specificity of the targeting. miR-218 inhibited significantly MACC1 protein expression, and consistently, MACC1-mediated migration, invasion and colony formation in CRC cells. Anti-miR-218 enhanced the MACC1-mediated migration, invasion and colony formation. Similar findings were observed in the gastric cancer cell line MKN-45. Further, we performed methylation-specific PCR of the SLIT2 and SLIT3 promoter, where miR-218 is encoded in intronic regions. The SLIT2 and SLIT3 promoters are hypermethylated in CRC cell lines. miR-218 and SLIT2 expressions correlated positively. Methyltransferase inhibitor 5-Azacytidine induced miR-218 expression and inhibited the expression of its target MACC1. We also determined that MACC1 has alternative polyadenylation (APA) sites, which results in different lengths of 3'-UTR variants in a CRC cell line. Taken together, miR-218 is post-transcriptionally inhibiting the MACC1 expression and its metastasis-inducing abilities.
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http://dx.doi.org/10.18632/oncotarget.10803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288198PMC
August 2016

Calcineurin regulates coordinated outgrowth of zebrafish regenerating fins.

Dev Cell 2014 Mar 20;28(5):573-87. Epub 2014 Feb 20.

DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany. Electronic address:

Vertebrates develop organs and appendages in a proportionally coordinated manner, and animals that regenerate them do so to the same dimensions as the original structures. Coordinated proportional growth involves controlled regulation between allometric and isometric growth programs, but it is unclear what executes this control. We show that calcineurin inhibition results in continued allometric outgrowth of regenerating fins beyond their original dimensions. Calcineurin inhibition also maintains allometric growth of juvenile fins and induces it in adult fins. Furthermore, calcineurin activity is low when the regeneration rate is highest, and its activity increases as the rate decreases. Growth measurements and morphometric analysis of proximodistal asymmetry indicate that calcineurin inhibition shifts fin regeneration from a distal growth program to a proximal program. This shift is associated with the promotion of retinoic acid signaling. Thus, we identified a calcineurin-mediated mechanism that operates as a molecular switch between position-associated isometric and allometric growth programs.
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http://dx.doi.org/10.1016/j.devcel.2014.01.019DOI Listing
March 2014

Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.

Neuro Oncol 2013 Dec 11;15(12):1696-709. Epub 2013 Nov 11.

Corresponding Author: Ulrike Stein, PhD, Experimental and Clinical Research Center, Charité University Medicine Berlin and the Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.

Background: Metastasis-associated in colon cancer 1 (MACC1) has been established as an independent prognostic indicator of metastasis formation and metastasis-free survival for patients with colon cancer and other solid tumors. However, no data are available concerning MACC1 expression in human astrocytic tumors. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor of adulthood, and due to its invasive and rapid growth, patients have unfavorable prognoses. Although these tumors rarely metastasize, their invasive and migratory behavior is similar to those of metastatic cells of tumors of different origin. Thus, we hypothesized that MACC1 may be involved in progression of human gliomas.

Methods: We performed real-time measurements of proliferation and migration in MACC1-transfected GBM cell lines (U138, U251) and evaluated tumor formation in organotypic hippocampal slice cultures of mice. Semiquantitative and quantitative real-time reverse transcription PCR analyses were performed for MACC1 and for its transcriptional target c-Met in human astrocytoma of World Health Organization grade II (low-grade astrocytoma) and GBM biopsies. Data were validated by MACC1 immunohistochemistry in independent matched samples of low-grade astrocytoma and GBM.

Results: MACC1 increases the proliferative, migratory, and tumor-formation abilities of GBM cells. The c-Met inhibitor crizotinib reduced MACC1-induced migration and tumor formation in organotypic hippocampal slice cultures of mice. Analyzing patients' biopsies, MACC1 expression increased concomitantly with increasing World Health Organization grade. Moreover, MACC1 expression levels allowed discrimination of dormant and recurrent low-grade astrocytomas and of primary and secondary GBM. Strong MACC1 expression correlated with reduced patient survival.

Conclusions: MACC1 may represent a promising biomarker for prognostication and a new target for treatment of human gliomas.
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http://dx.doi.org/10.1093/neuonc/not136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829600PMC
December 2013