Larsen Vornholz

Technical University of Munich

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Jürgen Ruland

German Cancer Research Center

Zsuzsanna Kurgyis

Technical University of Munich

Fabian J. Theis

Technical University of Munich

Katja Kranen

Technical University of Munich

Mark Mellett

University Hospital of Zurich

Tilo Biedermann

Technical University of Munich

Lajos V. Kemény

Harvard University

Lars E. French

Ludwig-Maximilians-Universität München

Shawn P. Kubli

University Health Network

Tak W. Mak

University Health Network

Cooperative Institutions

Technical University of Munich

Klinikum rechts der Isar

University of Bonn

German Cancer Research Center

Heidelberg University

Deutschen Konsortium für Translationale Krebsforschung

Princess Margaret Cancer Centre

Helmholtz Zentrum München

University Health Network

Ludwig-Maximilians-Universität München

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Decrypting drug actions and protein modifications by dose- and time-resolved proteomics

Science (2023)

Jana Zecha Florian Bayer Svenja Wiechmann Julia Rechenberger Nicola Berner

Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs. In this work, we introduce a proteomic assay called decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action. Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B cells by overactivating B cell receptor signaling. DecryptM profiling of 31 cancer drugs in 13 cell lines demonstrates the broad applicability of the approach. The resulting 1.8 million dose-response curves are provided as an interactive molecular resource in ProteomicsDB.

Drug action

Mechanism of Action

10.1126/science.ade3925

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Citations (52)

Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Hannah Theobald David Alejandro Bejarano Natalie Katzmarski Jessica Haub Jonas Schulte-Schrepping

Summary The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms which lead to the functional and developmental adaptation of lung-associated macrophages remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonal macrophage adaptation. Employing single-cell transcriptomics, high dimensional imaging and flow cytometric characterization paired to in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of Dectin-1 - Card9 signaling-dependent monocyte-derived macrophages (MoAM). MoAMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic and produced large amounts of interleukin 6 upon restimulation. Myeloid cell specific ApoE ablation inhibited monocyte to MoAM differentiation dependent on M-CSF secretion, promoting MoAM cell death thus impeding MoAM maintenance. In vivo , β-glucan-elicited MoAMs limited the bacterial burden of Legionella pneumophilia post infection and ameliorated fibrosis severity in a murine fibrosis model. Collectively these data identify MoAMs that are generated upon environmental cues and ApoE as an important determinant for lung immune resilience.

Ex vivo

Monocyte

Alveolar macrophage

10.1101/2022.09.15.505390

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ESDR333 - Keratinocyte-intrinsic BCL10/MALT1 activity initiates and amplifies psoriasiform skin inflammation

Zsuzsanna Kurgyis Larsen Vornholz Lajos V. Kemény Katja Kranen Mark Mellett

BCL10

10.26226/m.62fa009c7fa14e00183c0f6d

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Enforced CARD11/MALT1 signaling in dendritic cells triggers hemophagocytic lymphohistiocytosis

Proceedings of the National Academy of Sciences (2024)

Sophie E. Isay Larsen Vornholz Theresa Schnalzger Tanja Groll Thomas Magg

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome fueled by uncontrolled mononuclear phagocyte activity, yet the innate immune mechanisms driving HLH pathogenesis remain elusive. Germline gain-of-function (GOF) mutations in CARD11, a pivotal regulator of lymphocyte antigen receptor signaling, cause the lymphoproliferative disease B-cell expansion with NF-κB and T-cell anergy, which is frequently associated with HLH development. Given that CARD11 is physiologically expressed not only in lymphocytes but also in dendritic cells (DCs), we explored whether enforced CARD11 signaling in DCs contributes to immunopathology. We demonstrated that exclusive DC-intrinsic expression of CARD11-GOF in mice was sufficient to induce a lethal autoinflammatory syndrome that mimicked human HLH. Mechanistically, DC-intrinsic CARD11-GOF signaling triggered cell-autonomous inflammatory cytokine production via MALT1 paracaspase engagement. Genetic deletion of

Hemophagocytic Lymphohistiocytosis

10.1073/pnas.2413162121

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Nicheformer: A Foundation Model for Single-Cell and Spatial Omics

Anna C. Schaar Alejandro Tejada-Lapuerta Giovanni Palla Robert M. Gutgesell Lennard Halle

Tissue makeup relies fundamentally on the cellular microenvironment. Spatial single-cell genomics allows probing the underlying cellular interactions in an unbiased, scalable fashion. To learn a unified cell representation that accounts for local dependencies in the cellular microenvironment, we propose Nicheformer, a transformer-based foundation model that combines human and mouse dissociated single-cell and targeted spatial transcriptomics data. Pretrained on over 57 million dissociated and 53 million spatially resolved cells across 73 tissues, the model is fine-tuned on spatial tasks for spatial omics data to decode spatially resolved cellular information. Nicheformer excels in zero-shot-like and fine-tuning scenarios for a novel set of downstream tasks, in particular spatial composition prediction and spatial label prediction. Nicheformer enables the prediction of the spatial context of dissociated cells, allowing the transfer of rich spatial information to scRNA-seq datasets. Overall, Nicheformer sets the stage for the next generation of machine-learning models in spatial single-cell analysis.

Foundation (evidence)

Omics

10.2139/ssrn.4803291

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Citations (7)

Physiological and Pathological Functions of CARD9 Signaling in the Innate Immune System

Current topics in microbiology and immunology (2020)

Larsen Vornholz Jürgen Ruland

10.1007/82_2020_211

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Citations (26)

Fcmr regulates mononuclear phagocyte control of anti-tumor immunity

Nature Communications (2019)

Shawn P. Kubli Larsen Vornholz Gordon S. Duncan Wenjing Zhou Parameswaran Ramachandran

Abstract Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.

Mononuclear phagocyte system

10.1038/s41467-019-10619-w

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Citations (18)

Keratinocyte-intrinsic BCL10/MALT1 activity initiates and amplifies psoriasiform skin inflammation

Science Immunology (2021)

Zsuzsanna Kurgyis Larsen Vornholz Konstanze Pechloff Lajos V. Kemény Tim Wartewig

BCL10/MALT1 signaling in keratinocytes is altered in human sporadic psoriasis and is a critical initiator and amplifier of skin inflammation in mouse models.

BCL10

10.1126/sciimmunol.abi4425

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Citations (8)

Alpha1-antitrypsin impacts innate host–pathogen interactions with Candida albicans by stimulating fungal filamentation

Virulence (2024)

Martin Jaeger Axel Dietschmann Sophie Austermeier Sude Dinçer Pauline Porschitz

Our immune system possesses sophisticatedmechanisms to cope with invading microorganisms, while pathogensevolve strategies to deal with threats imposed by host immunity. Thehuman plasma protein α1-antitrypsin (AAT) exhibits pleiotropicimmune-modulating properties by both preventing immunopathology andimproving antimicrobial host defence. Genetic associations suggesteda role for AAT in candidemia, the most frequent fungal bloodstreaminfection in the ICU, yet little is known about how AAT influencesinteractions between Candidaalbicans and the immunesystem.

Filamentation

Fungal pathogen

10.1080/21505594.2024.2333367

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Citations (2)

Journal Club

BIOspektrum (2021)

Larsen Vornholz Johannes Sander Sabine Keuter Kirsten Küsel Julia Ast

Human genetics

10.1007/s12268-021-1651-z

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Citations (0)