Tim Ammon

Technical University of Munich

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Marc Schmidt‐Supprian

German Cancer Research Center

RÖ

Rupert Öllinger

Technical University of Munich

Katja Steiger

Technical University of Munich

Roland Rad

Technical University of Munich

Stefan Jentsch

Max Planck Institute of Biochemistry

Dieter Saur

German Cancer Research Center

Thomas Engleitner

Technical University of Munich

Günter Schneider

Universitätsmedizin Göttingen

Grzegorz M. Popowicz

Technical University of Munich

Alexander Strong

Wellcome Sanger Institute

Cooperative Institutions

Technical University of Munich

German Cancer Research Center

Klinikum rechts der Isar

Heidelberg University

Deutschen Konsortium für Translationale Krebsforschung

Ludwig-Maximilians-Universität München

Helmholtz Zentrum München

München Klinik

University of Cambridge

Max Planck Institute of Biochemistry

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Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia

Nature Communications (2018)

Maurizio Mangolini Frederik Götte A. P. Moore Tim Ammon Madlen Oelsner

Abstract The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-β mediated degradation of β-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises β-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells.

10.1038/s41467-018-06069-5

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Citations (59)

Role of Cdc48/p97 as a SUMO-targeted segregase curbing Rad51–Rad52 interaction

Nature Cell Biology (2013)

Steven Bergink Tim Ammon Maximilian J Kern Lothar Schermelleh Heinrich Leonhardt

RAD52

Chaperone (clinical)

10.1038/ncb2729

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Citations (124)

Assessing Liability and Legitimacy of School Transportation Services.

School business affairs (2011)

Tim Ammon Peggy Burns

Source

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Citations (0)

Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment

Nature Cancer (2022)

Chiara Falcomatà Stefanie Bärthel Sebastian A. Widholz Christian Schneeweis Juán José Montero

Immune checkpoint

Trametinib

10.1038/s43018-021-00326-1

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Citations (67)

Two for One.

American school & university (2006)

Tim Ammon Scott Little

Source

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The conserved ubiquitin-like protein Hub1 plays a critical role in splicing in human cells

Journal of Molecular Cell Biology (2014)

Tim Ammon Shravan Kumar Mishra Kaja Kowalska Grzegorz M. Popowicz Tad A. Holak

Different from canonical ubiquitin-like proteins, Hub1 does not form covalent conjugates with substrates but binds proteins non-covalently. In Saccharomyces cerevisiae, Hub1 associates with spliceosomes and mediates alternative splicing of SRC1, without affecting pre-mRNA splicing generally. Human Hub1 is highly similar to its yeast homolog, but its cellular function remains largely unexplored. Here, we show that human Hub1 binds to the spliceosomal protein Snu66 as in yeast; however, unlike its S. cerevisiae homolog, human Hub1 is essential for viability. Prolonged in vivo depletion of human Hub1 leads to various cellular defects, including splicing speckle abnormalities, partial nuclear retention of mRNAs, mitotic catastrophe, and consequently cell death by apoptosis. Early consequences of Hub1 depletion are severe splicing defects, however, only for specific splice sites leading to exon skipping and intron retention. Thus, the ubiquitin-like protein Hub1 is not a canonical spliceosomal factor needed generally for splicing, but rather a modulator of spliceosome performance and facilitator of alternative splicing.

Spliceosome

Exonic splicing enhancer

Splicing factor

Protein splicing

Polypyrimidine tract

Minor spliceosome

Exon skipping

Prp24

SR protein

10.1093/jmcb/mju026

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Citations (35)

PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice

Nature Communications (2019)

Julia Weber Jorge de la Rosa Carolyn Grove Markus Schick Lena Rad

Abstract B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7 , a transcription factor, and Phip , a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.

Functional Genomics

Genetic screen

10.1038/s41467-019-09180-3

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Citations (45)

Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection

Life Science Alliance (2019)

Julian J. Albers Tim Ammon Dario Gosmann Stefan Audehm Silvia Thoene

Adoptive transfer of TCR transgenic T cells holds great promise for treating various cancers. So far, mainly semi-randomly integrating vectors have been used to genetically modify T cells. These carry the risk of insertional mutagenesis, and the sole addition of an exogenous TCR potentially results in the mispairing of TCR chains with endogenous ones. Established approaches using nonviral vectors, such as transposons, already reduce the risk of insertional mutagenesis but have not accomplished site-specific integration. Here, we used CRISPR-Cas9 RNPs and adeno-associated virus 6 for gene targeting to deliver an engineered TCR gene specifically to the TCR alpha constant locus, thus placing it under endogenous transcriptional control. Our data demonstrate that this approach replaces the endogenous TCR, functionally redirects the edited T cells’ specificity in vitro , and facilitates potent tumor rejection in an in vivo xenograft model .

Insertional mutagenesis

Adoptive Cell Transfer

10.26508/lsa.201900367

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Citations (23)

Brief homogeneous TCR signals instruct common iNKT progenitors whose effector diversification is characterized by subsequent cytokine signaling

Immunity (2021)

Sabrina Bortoluzzi Nyambayar Dashtsoodol Thomas Engleitner Christoph Drees Sabine Helmrath

10.1016/j.immuni.2021.09.003

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Citations (27)

Role of the ubiquitin-like protein Hub1 in splice-site usage and alternative splicing