Bernd Wollscheid

Last Name

Wollscheid

First Name

Bernd

ORCID

0000-0002-3923-1610

Organisational unit

02072 - Proteomics Plattform D-HEST

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Publications 1 - 10 of 130

Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells
Kopecka, Joanna; Jacobs, Andrea; Frei, Andreas P.; et al. (2015)
Oncotarget
Multidrug resistance (MDR) in cancer cells is a challenging phenomenon often associated with P-glycoprotein (Pgp) surface expression. Finding new ways to bypass Pgp-mediated MDR still remains a daunting challenge towards the successful treatment of malignant neoplasms such as colorectal cancer. We applied the Cell Surface Capture technology to chemosensitive and chemoresistant human colon cancer to explore the cell surface proteome of Pgp-expressing cells in a discovery-driven fashion. Comparative quantitative analysis of identified cell surface glycoproteins revealed carbonic anhydrase type XII (CAXII) to be up-regulated on the surface of chemoresistant cells, similarly to Pgp. In cellular models showing an acquired MDR phenotype due to the selective pressure of chemotherapy, the progressive increase of the transcription factor hypoxia-inducible factor-1 alpha was paralleled by the simultaneous up-regulation of Pgp and CAXII. CAXII and Pgp physically interacted at the cell surface. CAXII silencing or pharmacological inhibition with acetazolamide decreased the ATPase activity of Pgp by altering the optimal pH at which Pgp operated and promoted chemosensitization to Pgp substrates in MDR cells. We propose CAXII as a new secondary marker of the MDR phenotype that influences Pgp activity directly and can be used as a pharmacological target for MDR research and potential treatment.
Proteomic analysis of Nogo-A KO mice
Montani, L.; Gerrits, B.; Gehrig, P.; et al. (2007)
Journal of Neurochemistry
Fc gamma receptors are expressed in the developing rat brain and activate downstream signaling molecules upon cross-linking with immune complex
Stamou, Marianna; Grodzki, Ana C.; Van Oostrum, Marc; et al. (2018)
Journal of Neuroinflammation
Background Exposure of the developing brain to immune mediators, including antibodies, is postulated to increase risk for neurodevelopmental disorders and neurodegenerative disease. It has been suggested that immunoglobulin G-immune complexes (IgG-IC) activate Fc gamma receptors (FcγR) expressed on neurons to modify signaling events in these cells. However, testing this hypothesis is hindered by a paucity of data regarding neuronal FcγR expression and function. Methods FcγR transcript expression in the hippocampus, cortex, and cerebellum of neonatal male and female rats was investigated ex vivo and in mixed cultures of primary hippocampal and cortical neurons and astrocytes using quantitative PCR analyses. Expression at the protein level in mixed cultures of primary hippocampal and cortical neurons and astrocytes was determined by immunocytochemistry, western blotting, proteotype analysis, and flow cytometry. The functionality of these receptors was assessed by measuring changes in intracellular calcium levels, Erk phosphorylation, and IgG internalization following stimulation with IgG-immune complexes. Results FcgrIa, FcgrIIa, FcgrIIb, FcgrIIIa, and Fcgrt transcripts were detectable in the cortex, hippocampus, and cerebellum at postnatal days 1 and 7. These transcripts were also present in primary hippocampal and cortical cell cultures, where their expression was modulated by IFNγ. Expression of FcγRIa, FcγRIIb, and FcγRIIIa, but not FcγRIIa or FcRn proteins, was confirmed in cultured hippocampal and cortical neurons and astrocytes at the single cell level. A subpopulation of these cells co-expressed the activating FcγRIa and the inhibitory FcγRIIb. Functional analyses demonstrated that exposure of hippocampal and cortical cell cultures to IgG-IC increases intracellular calcium and Erk phosphorylation and triggers FcγR-mediated internalization of IgG. Conclusions Our data demonstrate that developing neurons and astrocytes in the hippocampus and the cortex express signaling competent FcγR. These findings suggest that IgG antibodies may influence normal neurodevelopment or function via direct interactions with FcγR on non-immune cells in the brain.
Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
Wildschut, Mattheus Henricus Ernst; Mena, Julien; Dördelmann, Cyril; et al. (2023)
Nature Communications
Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
A tissue-specific atlas of protein-protein associations enables prioritization of candidate disease genes
Trip, Diederik S. Laman; van Oostrum, Marc; Memon, Danish; et al. (2025)
Nature Biotechnology
Despite progress in mapping protein-protein interactions, their tissue specificity is understudied. Here, given that protein coabundance is predictive of functional association, we compiled and analyzed protein abundance data of 7,811 proteomic samples from 11 human tissues to produce an atlas of tissue-specific protein associations. We find that this method recapitulates known protein complexes and the larger structural organization of the cell. Interactions of stable protein complexes are well preserved across tissues, while cell-type-specific cellular structures, such as synaptic components, are found to represent a substantial driver of differences between tissues. Over 25% of associations are tissue specific, of which <7% are because of differences in gene expression. We validate protein associations for the brain through cofractionation experiments in synaptosomes, curation of brain-derived pulldown data and AlphaFold2 modeling. We also construct a network of brain interactions for schizophrenia-related genes, indicating that our approach can functionally prioritize candidate disease genes in loci linked to brain disorders.
The Tumor Profiler Study: Integrated, multi-omic, functional tumor profiling for clinical decision support
Irmisch, Anja; Bonilla, Ximena; Chevrier, Stéphane; et al. (2020)
medRxiv
Recent technological advances allow profiling of tumor samples to an unparalleled level with respect to molecular and spatial composition as well as treatment response. We describe a prospective, observational clinical study performed within the Tumor Profiler (TuPro) Consortium that aims to show the extent to which such comprehensive information leads to advanced mechanistic insights of a patient’s tumor, enables prognostic and predictive biomarker discovery, and has the potential to support clinical decision making. For this study of melanoma, ovarian carcinoma, and acute myeloid leukemia tumors, in addition to the emerging standard diagnostic approaches of targeted NGS panel sequencing and digital pathology, we perform extensive characterization using the following exploratory technologies: single-cell genomics and transcriptomics, proteotyping, CyTOF, imaging CyTOF, pharmacoscopy, and 4i drug response profiling (4i DRP). In this work, we outline the aims of the TuPro study and present preliminary results on the feasibility of using these technologies in clinical practice showcasing the power of an integrative multi-modal and functional approach for understanding a tumor’s underlying biology and for clinical decision support.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialBASEC-Nr.2018-02050Funding StatementThe study described in this paper is the result of a jointly-funded effort between several academic institutions (The University of Zurich, The University of Zurich Hospital, The Swiss Federal Institute of Technology in Zurich, The University of Basel Hospital, and The University of Basel), as well as F. Hoffmann-La Roche AG.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe manuscript details a prospetive outlook for a study that is currently underway. However, the data will be made available upon study completion and publication.
Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia
Wegmann, Rebekka; Bonilla Bustillo, Ximena; Casanova, Ruben; et al. (2024)
Nature Communications
Deep single-cell multi-omic profiling offers a promising approach to understand and overcome drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML). Here, we combine single-cell ex vivo drug profiling (pharmacoscopy) with single-cell and bulk DNA, RNA, and protein analyses, alongside clinical data from 21 rrAML patients. Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research.
Mass spectrometry-based identification of VHL-regulated cellular membrane proteins in renal cell carcinoma
Boysen, Gunther; Wollscheid, Bernd; Bausch-Fluck, Damaris; et al. (2007)
Pathology, Research and Practice
A Peptidomimetic Antibiotic Interacts with the Periplasmic Domain of LptD from Pseudomonas aeruginosa
Andolina, Gloria; Bencze, László-Csaba; Zerbe, Katja; et al. (2018)
ACS Chemical Biology
Proteomic Exploration of the Cell Surface Landscape Reveals New Leukemia Associated Features
Bourquin, J. P.; Mirkowska, P.; Mejstrikova, E.; et al. (2012)
Blood

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