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Oncogenomics: Reuven Agami

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Reuven Agami Ph.D professorGroup leader, Head of Division

About Reuven Agami

Controlling cancer by RNA

Over the past years our main research objective was to understand the cancerous process in humans and identify essential cancerous genes and pathways. This is with the assumption that the knowledge obtained on these genes will allow us to design novel cancer therapeutic approaches. We developed an RNA interference (RNAi) approach to inactivate genes in mammalian cells and used it to identify potential novel human tumor suppressors (e.g. PITX1, BRD7, and RBM38) and to characterize in detail their mechanism of action and their role in cancer. Additionally, we initiated several genome-wide approaches to identify cancer causing microRNAs, an emerging gene family encoding for endogenous small non-coding RNAs. With these tools we discovered and characterized the role of the miR-372 family in tumor initiation and metastasis, and the oncogenic role of miR-221&222 and miR-135 in various types of cancers.

Very recently, we used expression and knockdown libraries of RNA binding proteins (RBPs) to search for those that regulate microRNA activity. We uncovered the existence of interplay between RBPs and microRNAs and described its impact on cellular differentiation, cell proliferation, and stress. Additionally, we generated unique genetic tools to study Alternative cleavage and polyadenylation of mRNAs (APA). With these tools we characterized the role of the gene PABPN1 as a suppressor of APA, and linked for the first time APA with a genetic disease caused by mutations in PABPN1. We further expanded this research line and now connect APA with cancer and study how APA affects protein translation and cellular behavior.

Last, we explore novel p53 functions. p53 is a prototype tumor suppressor gene mutated in more than half of human tumours. Our activities unravelled the binding of p53 to conserved genomic regions that possess all known hallmarks of enhancers of transcription. We show that p53 induces a unique type of non-protein coding RNAs (called enhancer-RNAs) from these loci to control the expression of distal genes. Moreover, we explore on a transcriptome scale the effect of p53 activation on protein translation. We propose that p53 activate a bimodal tumor-suppressive regulatory program in which proliferation arrest is imposed mainly at the transcriptional level, whereas cell growth is inhibited by global repression of the translation machinery through inhibition of the mTOR pathway. We now explore the tools we constructed in characterizing cancer metastasis and utilize our findings for cancer therapy.

 

Co-workers

Annibali, D

Daniela Annibali

Postdoctoral fellow

Experience

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Champagne, Julien

Julien Champagne

Postdoctoral fellow

Experience

I received my doctoral degree from Montpellier University (France) in 2018. During my PhD, I characterized the function of Cyclin D1 protein in the survival of healthy and cancer cells. To do so, in my previous team we developed a new hypersensitive protein detection method named Tandem-HTRF that could be used in clinics for diagnosis. We also used an upgraded version of RNA interference to uncover the clinical relevance of Cyclin D1 targeting in cancer cells. In October 2018, I joined the lab of Prof. Reuven Agami as a postdoctoral fellow. Here, my research interest is to understand how translation is regulated in cancer cells, especially after a specific amino-acid depletion.

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Dieter

Sebastian Dieter

Postdoctoral fellow

Experience

I am a physician scientist and work as a postdoc in the Oncogenomics department. As an MD by training, I specialized in internal medicine and hematology/oncology at the National Center for Tumor Diseases and the University Hospital in Heidelberg, Germany. My medical PhD was related to tumor-initiating cells in colorectal cancer, but beyond malignant stem cell biology I am very much interested in functional genomics and genomics-guided medicine. Currently I am using CRISPR- and other genome-wide screening approaches to better understand the dysregulation of transcription and translation in solid tumors.  

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Malka

Yuval Malka

Postdoctoral fellow

Experience

I arrived to Agami's lab after Ph.d and short Postdoc in the Hebrew University in Jerusalem. 

My major focus in my previous research was on processing metabolism of RNA. I arrived in to Agami's lab in November 2017 and in the present time; I'm focusing on various aspects of alternative polyadenylation and RNA modifications.

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533788 Pataskar -amended

Abhi Pataskar

Postdoctoral Fellow

Experience

I am presently starting my postdoctoral research in the lab of Prof. Reuven Agami. My research interest is to understand the selection and functions of enhancer elements in a systematic fashion to understanding fundamental principles of gene regulation and chromatin structure. In my PhD, I worked on understanding the role of DNA biophysics in priming the epigenetic state of the genomic segments.

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Blommaert, Naomi-2

Naomi Blommaert

Analist

Experience

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Nagel, Remco

Remco Nagel

Lab Manager

Experience

After doing my PhD in the Agami lab, screening for novel miRNA functions, I am now back in the lab where it all began. After 2 PostDoc projects at the VUmc and the NKI, where I used RNAi approaches and CRISPR technology to screen for novel combination therapies, I am now using these experiences to screen for elements for gene regulation and cancer therapy. Next to this, I am also the labmanager of the division of oncogenomics.

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Pierre-René Körner

Ph.D. student

Experience

My research interest lays in the fields of genetic regulations and the molecular basis of human disorders. After I received my master degree at the Radboud University Nijmegen  I joined the research group of Reuven Agami for my PhD. During the PhD my work will focus on bioinformatics analysis of
amino acid depletion and how it influences the regulation in cancer.

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Li, Li.JPG

Li Li

Ph.D. student

Personal details

Groups

Experience

I got my master degree of Biochemistry and Molecular Biology in Beijing Normal University and immediately joined Reuven Agami's lab for the PhD. I am working with projects about the identification of functional regulatory elements (lncRNAs, enhancers, CTCF) involved in oncogene-induced senescence and cancer. By studying this, It provides better understanding of the gene regulation network and cancer.

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Lovecchio, Domenica

Domenica Lovecchio

Ph.D. student

Experience

I am currently starting my PhD in the laboratory of Prof. R. Agami, where I will focus on functional genetic tools able to identify key players of cancer development. I got my master's degree in Genetics and Molecular Biology in Sapienza University of Rome, and I did three main internships around Europe.  During my scientific research I worked mainly on gene expression and immune system regulation. My last scientific project was supported by a competitive program at Pasteur Institute in Paris, where I studied the mechanisms that regulate the expression of RORγt transcription factor and the role of NFAT proteins.

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Kelly Mordente

Kelly Mordente

Ph.D. student

Experience

In January 2020, I joined the Agami lab as a PhD student. My research will focus on developing functional genetic tools to understand the role of amino acid depletion in cancer. Previously, I studied Biochemistry and Molecular Biology at UC Berkeley and later received my master degree in Pharmaceutical Sciences from Utrecht University.

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Research updates View All Updates

  • ERC-advanced project on enhancer RNAs

    2013:  Awarded an ERC-advanced project on enhancer RNAs

  • Awarded a KWF grant

    2013: Awarded a KWF grant to study protein translation in acquired resistance to cancer therapy.

Key publications View All Publications

  • eRNAs are required for p53-dependent enhancer activity and gene transcription

    Mol Cell. 2013; 49: 524-35

    Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, Elkon R, Melo SA, Léveillé N, Kalluri R, de Laat W, Agami R.



    Link to PubMed
  • The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites

    Cell. 2012; 149: 538-53

    Jenal M, Elkon R, Loayza-Puch F, van Haaften G, Kühn U, Menzies FM, OudeVrielink JA, Bos AJ, Drost J, Rooijers K, Rubinsztein DC, Agami R.

    Link to PubMed
 
 

Recent publications View All Publications

  • Characterization of noncoding regulatory DNA in the human genome

    Nat Biotechnol. 2017; 35(8):732-746

    Elkon R, Agami R.

    Link to PubMed
  • Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation

    Cell 2017;169(2):326-337

    Slobodin B., Han R., Calderone V., Vrielink J.A., Loayza-Puch R., Elkon R., Agami R.

    Link to PubMed
 

Contact

  • Office manager

    Elise Marseille

  • E-mail

    e.marseille@nki.nl

  • Telephone Number

    +31 20 512 2015

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