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Article: Forward Genetic Screens as Tools to Investigate Role and Mechanisms of EMT in Cancer.

Gasparics, Ákos / Sebe, Attila

2022 Volume 14, Issue 23

Abstract: Epithelial-mesenchymal transition (EMT) is a process of cellular plasticity regulated by complex signaling networks. Under physiological conditions, it plays an important role in wound healing and organ repair. Its importance for human disease is given ... ...

Abstract	Epithelial-mesenchymal transition (EMT) is a process of cellular plasticity regulated by complex signaling networks. Under physiological conditions, it plays an important role in wound healing and organ repair. Its importance for human disease is given by its central role in chronic fibroproliferative diseases and cancer, which represent leading causes of death worldwide. In tumors, EMT is involved in primary tumor growth, metastasis and therapy resistance. It is therefore a major requisite to investigate and understand the role of EMT and the mechanisms leading to EMT in order to tackle these diseases therapeutically. Forward genetic screens link genome modifications to phenotypes, and have been successfully employed to identify oncogenes, tumor suppressor genes and genes involved in metastasis or therapy resistance. In particular, transposon-based insertional mutagenesis screens and CRISPR-based screens are versatile and easy-to-use tools applied in recent years to discover and identify novel cancer-related mechanisms. Here, we review the contribution of forward genetic screens to our understanding of how EMT is regulated and how it is involved in various aspects of cancer. Based on the current literature, we propose these methods as additional tools to investigate EMT.
Language	English
Publishing date	2022-11-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14235928
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Article: A single amino acid switch converts the Sleeping Beauty transposase into an efficient unidirectional excisionase with utility in stem cell reprogramming

Miskey, Csaba / Zuliani, Cecilia Ines / Querques, Irma / Sebe, Attila / Wang, Yongming / Izsvak, Zsuzsanna / Barabas, Orsolya / Ivics, Zoltan

Nucleic acids research, 48(1):316-331

2019

Abstract: The Sleeping Beauty (SB) transposon is an advanced tool for genetic engineering and a useful model to investigate cut-and-paste DNA transposition in vertebrate cells. Here, we identify novel SB transposase mutants that display efficient and canonical ... ...

Institution	Paul-Ehrlich-Institut
Abstract	The Sleeping Beauty (SB) transposon is an advanced tool for genetic engineering and a useful model to investigate cut-and-paste DNA transposition in vertebrate cells. Here, we identify novel SB transposase mutants that display efficient and canonical excision but practically unmeasurable genomic re-integration. Based on phylogenetic analyses, we establish compensating amino acid replacements that fully rescue the integration defect of these mutants, suggesting epistasis between these amino acid residues. We further show that the transposons excised by the exc+/int− transposase mutants form extrachromosomal circles that cannot undergo a further round of transposition, thereby representing dead-end products of the excision reaction. Finally, we demonstrate the utility of the exc+/int− transposase in cassette removal for the generation of reprogramming factor-free induced pluripotent stem cells. Lack of genomic integration and formation of transposon circles following excision is reminiscent of signal sequence removal during V(D)J recombination, and implies that cut-and-paste DNA transposition can be converted to a unidirectional process by a single amino acid change.
Keywords	Gentechnologie ; Transposon
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article ; Online: Genetisch modifizierte regulatorische T-Zellen: Therapiekonzepte und ihr regulatorischer Rahmen.

Sebe, Attila / Anliker, Brigitte / Rau, Juliane / Renner, Matthias

Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz

2020 Volume 63, Issue 11, Page(s) 1403–1411

Abstract: Adoptive T‑cell therapies are emerging tools to combat various human diseases. CAR‑T cells are approved and marketed as last line therapeutics in advanced B‑cell lymphomas and leukemias. TCR-engineered T cells are being evaluated in clinical trials for a ...

Title translation	Genetically modified regulatory T cells: therapeutic concepts and regulatory aspects.
Abstract	Adoptive T‑cell therapies are emerging tools to combat various human diseases. CAR‑T cells are approved and marketed as last line therapeutics in advanced B‑cell lymphomas and leukemias. TCR-engineered T cells are being evaluated in clinical trials for a variety of hematological and solid tumors. Genetically modified regulatory T cells, however, are still in the initial stages of clinical development for the induction of immune tolerance in various indications.Here we outline the general role of regulatory T cells in establishing self-tolerance and the mechanisms by which these suppress the effector immune cells. Further, the role of regulatory T cells in the pathomechanism of certain immune diseases is presented, and the current status of clinical developments of genetically modified Treg cells is discussed. We also present the regulatory framework for genetically modified regulatory T cells as advanced therapy medicinal products, including aspects of manufacture and quality control, as well as nonclinical and clinical development requirements.
MeSH term(s)	Germany ; Humans ; Immunotherapy, Adoptive ; T-Lymphocytes, Regulatory
Language	German
Publishing date	2020-10-16
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1461973-8
ISSN	1437-1588 ; 1436-9990
ISSN (online)	1437-1588
ISSN	1436-9990
DOI	10.1007/s00103-020-03230-8
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Article ; Online: MRTFs- master regulators of EMT.

Gasparics, Ákos / Sebe, Attila

Developmental dynamics : an official publication of the American Association of Anatomists

2017 Volume 247, Issue 3, Page(s) 396–404

Abstract: Recent evidence implicates the myocardin-related transcription factors (MRTFs) as key mediators of the phenotypic plasticity leading to the conversion of various cell types into myofibroblasts. This review highlights the function of MRTFs during ... ...

Abstract	Recent evidence implicates the myocardin-related transcription factors (MRTFs) as key mediators of the phenotypic plasticity leading to the conversion of various cell types into myofibroblasts. This review highlights the function of MRTFs during development, fibrosis and cancer, and the role of MRTFs during epithelial-mesenchymal transitions (EMTs) underlying these processes. EMT is a sequentially orchestrated process where cells undergo a rearrangement of their cell contacts and activate a fibrogenic and myogenic expression program. MRTFs interact with and regulate the major signaling pathways and the expression of key markers and transcription factors involved in EMT. These functions indicate a central role for MRTFs in controlling the process of EMT. Developmental Dynamics 247:396-404, 2018. © 2017 Wiley Periodicals, Inc.
MeSH term(s)	Animals ; Epithelial-Mesenchymal Transition ; Fibrosis/pathology ; Humans ; Neoplasms/pathology ; Nuclear Proteins ; Signal Transduction ; Trans-Activators ; Transcription Factors/physiology
Chemical Substances	Nuclear Proteins ; Trans-Activators ; Transcription Factors ; myocardin
Language	English
Publishing date	2017-08-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.24544
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Article: Therapeutic Targeting of Fibrotic Epithelial-Mesenchymal Transition-An Outstanding Challenge.

Fintha, Attila / Gasparics, Ákos / Rosivall, László / Sebe, Attila

Frontiers in pharmacology

2019 Volume 10, Page(s) 388

Abstract: Back in 1995, a landmark paper was published, which shaped the fibrosis literature for many years to come. During the characterization of a fibroblast-specific marker (FSP1) in the kidneys, an observation was made, which gave rise to the hypothesis that " ...

Abstract	Back in 1995, a landmark paper was published, which shaped the fibrosis literature for many years to come. During the characterization of a fibroblast-specific marker (FSP1) in the kidneys, an observation was made, which gave rise to the hypothesis that "fibroblasts in some cases arise from the local conversion of epithelium." In the following years, epithelial-mesenchymal transition was in the spotlight of fibrosis research, especially in the kidney. However, the hypothesis came under scrutiny following some discouraging findings from lineage tracing experiments and clinical observations. In this review, we provide a timely overview of the current position of the epithelial-mesenchymal transition hypothesis in the context of fibrosis (with a certain focus on renal fibrosis) and highlight some of the potential hurdles and pitfalls preventing therapeutic breakthroughs targeting fibrotic epithelial-mesenchymal transition.
Language	English
Publishing date	2019-04-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2019.00388
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Article ; Online: Reprogramming of Human Fibroblasts to Induced Pluripotent Stem Cells with Sleeping Beauty Transposon-Based Stable Gene Delivery.

Sebe, Attila / Ivics, Zoltán

Methods in molecular biology (Clifton, N.J.)

2016 Volume 1400, Page(s) 419–427

Abstract: Human induced pluripotent stem (iPS) cells are a source of patient-specific pluripotent stem cells and resemble human embryonic stem (ES) cells in gene expression profiles, morphology, pluripotency, and in vitro differentiation potential. iPS cells are ... ...

Abstract	Human induced pluripotent stem (iPS) cells are a source of patient-specific pluripotent stem cells and resemble human embryonic stem (ES) cells in gene expression profiles, morphology, pluripotency, and in vitro differentiation potential. iPS cells are applied in disease modeling, drug screenings, toxicology screenings, and autologous cell therapy. In this protocol, we describe how to derive human iPS cells from fibroblasts by Sleeping Beauty (SB) transposon-mediated gene transfer of reprogramming factors. First, the components of the non-viral Sleeping Beauty transposon system, namely a transposon vector encoding reprogramming transcription factors and a helper plasmid expressing the SB transposase, are electroporated into human fibroblasts. The reprogramming cassette undergoes transposition from the transfected plasmids into the fibroblast genome, thereby resulting in stable delivery of the reprogramming factors. Reprogramming by using this protocol takes ~4 weeks, after which the iPS cells are isolated and clonally propagated.
MeSH term(s)	Cell Transdifferentiation/genetics ; Cellular Reprogramming ; Cellular Reprogramming Techniques ; DNA Transposable Elements ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Gene Transfer Techniques ; Genetic Vectors/genetics ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-3372-3_26
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Article ; Online: In Vitro Insertional Mutagenesis Screen Identifies Novel Genes Driving Breast Cancer Metastasis.

Miskey, Csaba / Botezatu, Lacramioara / Temiz, Nuri A / Gogol-Döring, Andreas / Bartha, Áron / Győrffy, Balázs / Largaespada, David A / Ivics, Zoltán / Sebe, Attila

Molecular cancer research : MCR

2022 Volume 20, Issue 10, Page(s) 1502–1515

Abstract: Metastasis, a complex, multistep process, is responsible for the overwhelming majority of cancer-related deaths. Despite its devastating consequences, it is not possible to effectively treat cancer that has spread to vital organs, the mechanisms leading ... ...

Abstract	Metastasis, a complex, multistep process, is responsible for the overwhelming majority of cancer-related deaths. Despite its devastating consequences, it is not possible to effectively treat cancer that has spread to vital organs, the mechanisms leading to metastasis are still poorly understood, and the catalog of metastasis promoting genes is still incomprehensive. To identify new driver genes of metastasis development, we performed an in vitro Sleeping Beauty transposon-based forward genetic screen in nonmetastatic SKBR3 human breast cancer cells. Boyden chamber-based matrix invasion assays were used to harvest cells that acquired a de novo invasive phenotype. Using targeted RNA sequencing data from 18 pools of invasive cells, we carried out a gene-centric candidate gene prediction and identified established and novel metastasis driver genes. Analysis of these genes revealed their association with metastasis related processes and we further established their clinical relevance in metastatic breast cancer. Two novel candidate genes, G protein-coupled receptor kinase interacting ArfGAP 2 (GIT2) and muscle-associated receptor tyrosine kinase (MUSK), were functionally validated as metastasis driver genes in a series of in vitro and in vivo experimental metastasis models. We propose that our robust and scalable approach will be a useful addition to the toolkit of methodologic resources used to identify genes driving cancer metastasis. Implications: Novel metastasis drivers were identified in a human breast cancer cell line by performing an in vitro, Sleeping Beauty transposon-based forward genetic screen and an RNA fusion-based candidate gene prediction.
MeSH term(s)	Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; DNA Transposable Elements/genetics ; Female ; Humans ; Mutagenesis ; Mutagenesis, Insertional ; Protein-Tyrosine Kinases/genetics ; RNA ; Receptors, G-Protein-Coupled/genetics
Chemical Substances	DNA Transposable Elements ; Receptors, G-Protein-Coupled ; RNA (63231-63-0) ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2022-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-21-0772
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Article ; Online: Regulatory Considerations for Clinical Trial Applications with CRISPR-Based Medicinal Products.

Anliker, Brigitte / Childs, Liam / Rau, Juliane / Renner, Matthias / Schüle, Silke / Schuessler-Lenz, Martina / Sebe, Attila

The CRISPR journal

2022 Volume 5, Issue 3, Page(s) 364–376

Abstract: Since first proposed as a new tool for gene targeting and genome editing, CRISPR technology has quickly advanced into the clinical stage. Initial studies highlight the potential for CRISPR-Cas9-mediated therapeutic approaches in human medicine to correct ...

Abstract	Since first proposed as a new tool for gene targeting and genome editing, CRISPR technology has quickly advanced into the clinical stage. Initial studies highlight the potential for CRISPR-Cas9-mediated therapeutic approaches in human medicine to correct incurable genetic diseases and enhance cell-based therapeutic approaches. While acknowledging the opportunities this technology brings for the treatment of patients with severe diseases, timely development of these innovative medicinal products requires regulatory oversight and adaptation of regulatory requirements to ensure the safety and efficacy of medicinal products based on CRISPR technology. We briefly present the current regulatory framework applicable for CRISPR-Cas-based developments as advanced therapy medicinal products. Moreover, scientific- and regulatory-driven considerations relevant for advancing product development toward clinical trial applications in Germany are highlighted by discussing the key aspects of quality and nonclinical and clinical development requirements.
MeSH term(s)	CRISPR-Cas Systems/genetics ; Clinical Trials as Topic ; Gene Editing ; Gene Targeting ; Humans
Language	English
Publishing date	2022-04-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	3017891-5
ISSN	2573-1602 ; 2573-1599
ISSN (online)	2573-1602
ISSN	2573-1599
DOI	10.1089/crispr.2021.0148
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Article ; Online: When the endothelium scores an own goal: endothelial cells actively augment metastatic extravasation through endothelial-mesenchymal transition.

Gasparics, Ákos / Rosivall, László / Krizbai, István A / Sebe, Attila

American journal of physiology. Heart and circulatory physiology

2016 Volume 310, Issue 9, Page(s) H1055–63

Abstract: Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an ... ...

Abstract	Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.
MeSH term(s)	Animals ; Cell Communication ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Epithelial-Mesenchymal Transition ; Humans ; Neoplasm Metastasis ; Neoplasms/metabolism ; Neoplasms/pathology ; Signal Transduction ; Transendothelial and Transepithelial Migration ; Tumor Microenvironment
Language	English
Publishing date	2016-03-18
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00042.2016
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Article: The impact of transposable element activity on therapeutically relevant human stem cells.

Schumann, Gerald G / Fuchs, Nina V / Tristán-Ramos, Pablo / Sebe, Attila / Ivics, Zoltán / Heras, Sara R

Mobile DNA

2019 Volume 10, Page(s) 9

Abstract: Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers ... ...

Abstract	Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapies.
Language	English
Publishing date	2019-03-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2536054-1
ISSN	1759-8753
ISSN	1759-8753
DOI	10.1186/s13100-019-0151-x
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