Publications by authors named "Liselot M Mus"

7 Publications

  • Page 1 of 1

Recurrent chromosomal imbalances provide selective advantage to human embryonic stem cells under enhanced replicative stress conditions.

Genes Chromosomes Cancer 2021 Apr 9;60(4):272-281. Epub 2021 Jan 9.

Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.

Human embryonic stem cells (hESCs) and embryonal tumors share a number of common features, including a compromised G1/S checkpoint. Consequently, these rapidly dividing hESCs and cancer cells undergo elevated levels of replicative stress, inducing genomic instability that drives chromosomal imbalances. In this context, it is of interest that long-term in vitro cultured hESCs exhibit a remarkable high incidence of segmental DNA copy number gains, some of which are also highly recurrent in certain malignancies such as 17q gain (17q+). The selective advantage of DNA copy number changes in these cells has been attributed to several underlying processes including enhanced proliferation. We hypothesized that these recurrent chromosomal imbalances become rapidly embedded in the cultured hESCs through a replicative stress driven Darwinian selection process. To this end, we compared the effect of hydroxyurea-induced replicative stress vs normal growth conditions in an equally mixed cell population of isogenic euploid and 17q + hESCs. We could show that 17q + hESCs rapidly overtook normal hESCs. Our data suggest that recurrent chromosomal segmental gains provide a proliferative advantage to hESCs under increased replicative stress, a process that may also explain the highly recurrent nature of certain imbalances in cancer.
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http://dx.doi.org/10.1002/gcc.22931DOI Listing
April 2021

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness.

Sci Rep 2020 01 14;10(1):218. Epub 2020 Jan 14.

Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.

Neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. The low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates that ALK-activating mutations are present in 10% of primary tumours. Together with other mutations causing RAS/MAPK pathway activation, ALK mutations are also enriched in relapsed cases and ALK activation was shown to accelerate MYCN-driven tumour formation through hitherto unknown ALK-driven target genes. To gain further insight into how ALK contributes to neuroblastoma aggressiveness, we searched for known oncogenes in our previously reported ALK-driven gene signature. We identified ETV5, a bona fide oncogene in prostate cancer, as robustly upregulated in neuroblastoma cells harbouring ALK mutations, and show high ETV5 levels downstream of the RAS/MAPK axis. Increased ETV5 expression significantly impacted migration, invasion and colony formation in vitro, and ETV5 knockdown reduced proliferation in a murine xenograft model. We also established a gene signature associated with ETV5 knockdown that correlates with poor patient survival. Taken together, our data highlight ETV5 as an intrinsic component of oncogenic ALK-driven signalling through the MAPK axis and propose that ETV5 upregulation in neuroblastoma may contribute to tumour aggressiveness.
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http://dx.doi.org/10.1038/s41598-019-57076-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959226PMC
January 2020

ALK positively regulates MYCN activity through repression of HBP1 expression.

Oncogene 2019 04 11;38(15):2690-2705. Epub 2018 Dec 11.

Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.

ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the 'HMG-box transcription factor 1' (HBP1) through the PIK-AKT-FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PIK antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.
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http://dx.doi.org/10.1038/s41388-018-0595-3DOI Listing
April 2019

Vehicle development, pharmacokinetics and toxicity of the anti-invasive agent 4-fluoro-3',4',5'-trimethoxychalcone in rodents.

PLoS One 2018 22;13(2):e0192548. Epub 2018 Feb 22.

Cancer Research Institute Ghent (CRIG), Ghent, Belgium.

Effective inhibitors of invasion and metastasis represent a serious unmet clinical need. We have recently identified 4-fluoro-3',4',5'-trimethoxychalcone or C16 as a potent anti-invasive molecule. In this paper, we report on the development of an optimized vehicle for oral administration of C16. We also explore its pharmacokinetic and toxicity profile in rodents as a prelude to a broad-scope evaluation as a pharmacological tool in animal models of disease. C16 showed suboptimal pharmacokinetics with limited oral bioavailability and whole blood stability. Rapid metabolism with elimination via glutathione conjugation was observed. An oral dosing routine using medicated gels was developed to overcome bioavailability issues and yielded sustained whole blood levels above the half maximal effective concentration (EC50) in a 7-day study. The compound proved well-tolerated in acute and chronic experiments at 300 mg/kg PO dosing. The medicated gel formulation is highly suitable for evaluation of C16 in animal models of disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192548PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823406PMC
April 2018

EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research.

Authors:
Jan Van Deun Pieter Mestdagh Patrizia Agostinis Özden Akay Sushma Anand Jasper Anckaert Zoraida Andreu Martinez Tine Baetens Els Beghein Laurence Bertier Geert Berx Janneke Boere Stephanie Boukouris Michel Bremer Dominik Buschmann James B Byrd Clara Casert Lesley Cheng Anna Cmoch Delphine Daveloose Eva De Smedt Seyma Demirsoy Victoria Depoorter Bert Dhondt Tom A P Driedonks Aleksandra Dudek Abdou Elsharawy Ilaria Floris Andrew D Foers Kathrin Gärtner Abhishek D Garg Edward Geeurickx Jan Gettemans Farzaneh Ghazavi Bernd Giebel Tom Groot Kormelink Grace Hancock Hetty Helsmoortel Andrew F Hill Vincent Hyenne Hina Kalra David Kim Joanna Kowal Sandra Kraemer Petra Leidinger Carina Leonelli Yaxuan Liang Lien Lippens Shu Liu Alessandra Lo Cicero Shaun Martin Suresh Mathivanan Prabhu Mathiyalagan Támas Matusek Gloria Milani Marta Monguió-Tortajada Liselot M Mus Dillon C Muth Andrea Németh Esther N M Nolte-'t Hoen Lorraine O'Driscoll Roberta Palmulli Michael W Pfaffl Bjarke Primdal-Bengtson Erminia Romano Quentin Rousseau Susmita Sahoo Natalia Sampaio Monisha Samuel Benjamin Scicluna Bieke Soen Anneleen Steels Johannes V Swinnen Maarit Takatalo Safia Thaminy Clotilde Théry Joeri Tulkens Isabel Van Audenhove Susanne van der Grein Alan Van Goethem Martijn J van Herwijnen Guillaume Van Niel Nadine Van Roy Alexander R Van Vliet Niels Vandamme Suzanne Vanhauwaert Glenn Vergauwen Frederik Verweij Annelynn Wallaert Marca Wauben Kenneth W Witwer Marijke I Zonneveld Olivier De Wever Jo Vandesompele An Hendrix

Nat Methods 2017 02;14(3):228-232

Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.

We argue that the field of extracellular vesicle (EV) biology needs more transparent reporting to facilitate interpretation and replication of experiments. To achieve this, we describe EV-TRACK, a crowdsourcing knowledgebase (http://evtrack.org) that centralizes EV biology and methodology with the goal of stimulating authors, reviewers, editors and funders to put experimental guidelines into practice.
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http://dx.doi.org/10.1038/nmeth.4185DOI Listing
February 2017

Depletion of tRNA-halves enables effective small RNA sequencing of low-input murine serum samples.

Sci Rep 2016 11 30;6:37876. Epub 2016 Nov 30.

Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium.

The ongoing ascent of sequencing technologies has enabled researchers to gain unprecedented insights into the RNA content of biological samples. MiRNAs, a class of small non-coding RNAs, play a pivotal role in regulating gene expression. The discovery that miRNAs are stably present in circulation has spiked interest in their potential use as minimally-invasive biomarkers. However, sequencing of blood-derived samples (serum, plasma) is challenging due to the often low RNA concentration, poor RNA quality and the presence of highly abundant RNAs that dominate sequencing libraries. In murine serum for example, the high abundance of tRNA-derived small RNAs called 5' tRNA halves hampers the detection of other small RNAs, like miRNAs. We therefore evaluated two complementary approaches for targeted depletion of 5' tRNA halves in murine serum samples. Using a protocol based on biotinylated DNA probes and streptavidin coated magnetic beads we were able to selectively deplete 95% of the targeted 5' tRNA half molecules. This allowed an unbiased enrichment of the miRNA fraction resulting in a 6-fold increase of mapped miRNA reads and 60% more unique miRNAs detected. Moreover, when comparing miRNA levels in tumor-carrying versus tumor-free mice, we observed a three-fold increase in differentially expressed miRNAs.
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http://dx.doi.org/10.1038/srep37876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129013PMC
November 2016

Chick Heart Invasion Assay for Testing the Invasiveness of Cancer Cells and the Activity of Potentially Anti-invasive Compounds.

J Vis Exp 2015 Jun 6(100):e52792. Epub 2015 Jun 6.

Department of Radiation Oncology and Experimental Cancer Research, University of Ghent.

The goal of the chick heart assay is to offer a relevant organ culture method to study tumor invasion in three dimensions. The assay can distinguish between invasive and non-invasive cells, and enables study of the effects of test compounds on tumor invasion. Cancer cells - either as aggregates or single cells - are confronted with fragments of embryonic chick heart. After organ culture in suspension for a few days or weeks the confronting cultures are fixed and embedded in paraffin for histological analysis. The three-dimensional interaction between the cancer cells and the normal tissue is then reconstructed from serial sections stained with hematoxylin-eosin or after immunohistochemical staining for epitopes in the heart tissue or the confronting cancer cells. The assay is consistent with the recent concept that cancer invasion is the result of molecular interactions between the cancer cells and their neighbouring stromal host elements (myofibroblasts, endothelial cells, extracellular matrix components, etc.). Here, this stromal environment is offered to the cancer cells as a living tissue fragment. Supporting aspects to the relevance of the assay are multiple. Invasion in the assay is in accordance with the criteria of cancer invasion: progressive occupation and replacement in time and space of the host tissue, and invasiveness and non-invasiveness in vivo of the confronting cells generally correlates with the outcome of the assay. Furthermore, the invasion pattern of cells in vivo, as defined by pathologists, is reflected in the histological images in the assay. Quantitative structure-activity relation (QSAR) analysis of the results obtained with numerous potentially anti-invasive organic congener compounds allowed the study of structure-activity relations for flavonoids and chalcones, and known anti-metastatic drugs used in the clinic (e.g., microtubule inhibitors) inhibit invasion in the assay as well. However, the assay does not take into account immunological contributions to cancer invasion.
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http://dx.doi.org/10.3791/52792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544965PMC
June 2015