J Paul Werthenbach

University of Cologne

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Fabian Schorn

University of Cologne

Lars M. Schiffmann

University Hospital Cologne

Hamid Kashkar

University of Cologne

Manolis Pasparakis

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Jens M. Seeger

University of Cologne

Domagoj Vucic

St Andrew's Healthcare

Martin Krönke

University of Cologne

Marie‐Christine Albert

University of Cologne

Saskia Diana Günther

University Hospital Cologne

Christiane J. Bruns

University Hospital Cologne

Cooperative Institutions

University of Cologne

University Hospital Cologne

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Klinik und Poliklinik für Psychosomatik und Psychotherapie

Centrum für Integrierte Onkologie

Institute of Medical Microbiology and Hygiene

LVR-Klinik Köln

Heinrich Heine University Düsseldorf

Integrated Oncology (United States)

Düsseldorf University Hospital

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Elevated X-linked inhibitor of apoptosis protein (XIAP) expression uncovers detrimental prognosis in subgroups of neoadjuvant treated and T-cell rich esophageal adenocarcinoma

BMC Cancer (2019)

Lars M. Schiffmann Heike Göbel Heike Löser Fabian Schorn J Paul Werthenbach

Molecular markers predicting survival in esophageal adenocarcinoma (EAC) are rare. Specifically, in favorable oncologic situations, e.g. nodal negativity or major neoadjuvant therapy response, there is a lack of additional risk factors that serve to predict patients' outcome more precisely. This study evaluated X-linked inhibitor of apoptosis protein (XIAP) as a potential marker improving outcome prediction.Tissue microarrays from 362 patients that were diagnosed with resectable EAC were included in the study. XIAP was stained by immunohistochemistry and correlated to clinical outcome, molecular markers and markers of the cellular tumor microenvironment.XIAP did not impact on overall survival (OS) in the whole study collective. Subgroup analyses stratifying for common genetic markers (TP53, ERBB2, ARID1A/SWI/SNF) did not disclose any impact of XIAP expression on survival. Detailed subgroup analyses of [1] nodal negative patients, [2] highly T-cell infiltrated tumors and [3] therapy responders to neoadjuvant treatment revealed a significant inverse role of high XIAP expression in these specific oncologic situations; elevated XIAP expression detrimentally affected patients' outcome in these subgroups. [1]: OS XIAP low: 202 months (m) vs. XIAP high: 38 m; [2]: OS 116 m vs. 28.2 m; [3]: OS 31 m vs. 4 m).Our data suggest XIAP expression in EAC as a worthy tool to improve outcome prediction in specific oncologic settings that might directly impact on clinical diagnosis and treatment of EAC in the future.

XIAP

Surgical oncology

Tissue microarray

Inhibitor of apoptosis

10.1186/s12885-019-5722-1

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Citations (19)

cIAPs control RIPK1 kinase activity‐dependent and ‐independent cell death and tissue inflammation

The EMBO Journal (2023)

Fabian Schorn J Paul Werthenbach M. Hoffmann Mila Daoud Johanna Stachelscheid

Abstract Cellular inhibitor of apoptosis proteins (cIAPs) are RING‐containing E3 ubiquitin ligases that ubiquitylate receptor‐interacting protein kinase 1 (RIPK1) to regulate TNF signalling. Here, we established mice simultaneously expressing enzymatically inactive cIAP1/2 variants, bearing mutations in the RING domains of cIAP1/2 (cIAP1/2 mutant RING, cIAP1/2 MutR ). cIap1/2 MutR/MutR mice died during embryonic development due to RIPK1‐mediated apoptosis. While expression of kinase‐inactive RIPK1 D138N rescued embryonic development, Ripk1 D138N/D138N /cIap1/2 MutR/MutR mice developed systemic inflammation and died postweaning. Cells expressing cIAP1/2 MutR and RIPK1 D138N were still susceptible to TNF‐induced apoptosis and necroptosis, implying additional kinase‐independent RIPK1 activities in regulating TNF signalling. Although further ablation of Ripk3 did not lead to any phenotypic improvement, Tnfr1 gene knock‐out prevented early onset of systemic inflammation and premature mortality, indicating that cIAPs control TNFR1‐mediated toxicity independent of RIPK1 and RIPK3. Beyond providing novel molecular insights into TNF‐signalling, the mouse model established in this study can serve as a useful tool to further evaluate ongoing therapeutic protocols using inhibitors of TNF, cIAPs and RIPK1.

RIPK1

10.15252/embj.2023113614

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Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Nature Communications (2020)

Lars M. Schiffmann J Paul Werthenbach F. Heintges-Kleinhofer J. M. Seeger Melanie Fritsch

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

Reprogramming

Bioenergetics

10.1038/s41467-020-17472-2

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Citations (54)

Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

Nature (2019)

Melanie Fritsch Saskia Diana Günther Robin Schwarzer Marie‐Christine Albert Fabian Schorn

Pyroptosis

Caspase 8

Knockout mouse

10.1038/s41586-019-1770-6

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XIAP promotes melanoma growth by inducing tumour neutrophil infiltration

EMBO Reports (2022)

Mila Daoud Pia Nora Broxtermann Fabian Schorn J Paul Werthenbach Jens M. Seeger

Elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti-apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro-inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up-regulation and secretion of chemokines such as IL8, that are responsible for intra-tumour neutrophil accumulation. Alteration of the XIAP-RIPK2-TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer.

Infiltration (HVAC)

XIAP

10.15252/embr.202153608

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Citations (18)