Rudolf Aebersold

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Aebersold

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Rudolf

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0000-0002-9576-3267

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Publications 1 - 10 of 120

Longevity interventions modulate mechanotransduction and extracellular matrix homeostasis in C. elegans
Teuscher, Alina C.; Statzer, Cyril; Goyala, Anita; et al. (2024)
Nature Communications
Dysfunctional extracellular matrices (ECM) contribute to aging and disease. Repairing dysfunctional ECM could potentially prevent age-related pathologies. Interventions promoting longevity also impact ECM gene expression. However, the role of ECM composition changes in healthy aging remains unclear. Here we perform proteomics and in-vivo monitoring to systematically investigate ECM composition (matreotype) during aging in C. elegans revealing three distinct collagen dynamics. Longevity interventions slow age-related collagen stiffening and prolong the expression of collagens that are turned over. These prolonged collagen dynamics are mediated by a mechanical feedback loop of hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression and longevity via the transcriptional co-activator YAP-1 across tissues. Our results provide in-vivo evidence that coordinated ECM remodeling through mechanotransduction is required and sufficient to promote longevity, offering potential avenues for interventions targeting ECM dynamics.
Generic Comparison of Protein Inference Engines
Claassen, Manfred; Reiter, Lukas; Hengartner, Michael; et al. (2012)
Molecular & Cellular Proteomics
Protein identifications, instead of peptide-spectrum matches, constitute the biologically relevant result of shotgun proteomics studies. How to appropriately infer and report protein identifications has triggered a still ongoing debate. This debate has so far suffered from the lack of appropriate performance measures that allow us to objectively assess protein inference approaches. This study describes an intuitive, generic and yet formal performance measure and demonstrates how it enables experimentalists to select an optimal protein inference strategy for a given collection of fragment ion spectra. We applied the performance measure to systematically explore the benefit of excluding possibly unreliable protein identifications, such as single-hit wonders. Therefore, we defined a family of protein inference engines by extending a simple inference engine by thousands of pruning variants, each excluding a different specified set of possibly unreliable identifications. We benchmarked these protein inference engines on several data sets representing different proteomes and mass spectrometry platforms. Optimally performing inference engines retained all high confidence spectral evidence, without posterior exclusion of any type of protein identifications. Despite the diversity of studied data sets consistently supporting this rule, other data sets might behave differently. In order to ensure maximal reliable proteome coverage for data sets arising in other studies we advocate abstaining from rigid protein inference rules, such as exclusion of single-hit wonders, and instead consider several protein inference approaches and assess these with respect to the presented performance measure in the specific application context.
A High-Confidence Human Plasma Proteome Reference Set with Estimated Concentrations in PeptideAtlas
Farrah, Terry; Deutsch, Eric W.; Omenn, Gilbert S.; et al. (2011)
Molecular & Cellular Proteomics
Human blood plasma can be obtained relatively noninvasively and contains proteins from most, if not all, tissues of the body. Therefore, an extensive, quantitative catalog of plasma proteins is an important starting point for the discovery of disease biomarkers. In 2005, we showed that different proteomics measurements using different sample preparation and analysis techniques identify significantly different sets of proteins, and that a comprehensive plasma proteome can be compiled only by combining data from many different experiments. Applying advanced computational methods developed for the analysis and integration of very large and diverse data sets generated by tandem MS measurements of tryptic peptides, we have now compiled a high-confidence human plasma proteome reference set with well over twice the identified proteins of previous high-confidence sets. It includes a hierarchy of protein identifications at different levels of redundancy following a clearly defined scheme, which we propose as a standard that can be applied to any proteomics data set to facilitate cross-proteome analyses. Further, to aid in development of blood-based diagnostics using techniques such as selected reaction monitoring, we provide a rough estimate of protein concentrations using spectral counting. We identified 20,433 distinct peptides, from which we inferred a highly nonredundant set of 1929 protein sequences at a false discovery rate of 1%. We have made this resource available via PeptideAtlas, a large, multiorganism, publicly accessible compendium of peptides identified in tandem MS experiments conductedby laboratories around the world.
The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support
Irmisch, Anja; Bonilla, Ximena; Lehmann, Kjong-Van; et al. (2021)
Cancer Cell
The application and integration of molecular profiling technologies create novel opportunities for personalized medicine. Here, we introduce the Tumor Profiler Study, an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease.
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.
Initial recommendations for performing, benchmarking and reporting single-cell proteomics experiments
Gatto, Laurent; Aebersold, Rudolf; Cox, Juergen; et al. (2023)
Nature Methods
Analyzing proteins from single cells by tandem mass spectrometry (MS) has recently become technically feasible. While such analysis has the potential to accurately quantify thousands of proteins across thousands of single cells, the accuracy and reproducibility of the results may be undermined by numerous factors affecting experimental design, sample preparation, data acquisition and data analysis. We expect that broadly accepted community guidelines and standardized metrics will enhance rigor, data quality and alignment between laboratories. Here we propose best practices, quality controls and data-reporting recommendations to assist in the broad adoption of reliable quantitative workflows for single-cell proteomics. Resources and discussion forums are available at https://single-cell.net/guidelines.
Detection of isoforms and genomic alterations by high-throughput full-length single-cell RNA sequencing in ovarian cancer
Dondi, Arthur; Lischetti, Ulrike; Jacob, Francis; et al. (2023)
Nature Communications
Understanding the complex background of cancer requires genotype-phenotype information in single-cell resolution. Here, we perform long-read single-cell RNA sequencing (scRNA-seq) on clinical samples from three ovarian cancer patients presenting with omental metastasis and increase the PacBio sequencing depth to 12,000 reads per cell. Our approach captures 152,000 isoforms, of which over 52,000 were not previously reported. Isoform-level analysis accounting for non-coding isoforms reveals 20% overestimation of protein-coding gene expression on average. We also detect cell type-specific isoform and poly-adenylation site usage in tumor and mesothelial cells, and find that mesothelial cells transition into cancer-associated fibroblasts in the metastasis, partly through the TGF-β/miR-29/Collagen axis. Furthermore, we identify gene fusions, including an experimentally validated IGF2BP2::TESPA1 fusion, which is misclassified as high TESPA1 expression in matched short-read data, and call mutations confirmed by targeted NGS cancer gene panel results. With these findings, we envision long-read scRNA-seq to become increasingly relevant in oncology and personalized medicine.
Feasibility of multiomics tumor profiling for guiding treatment of melanoma
Miglino, Nicola; Toussaint, Nora Christina; Ring, Alexander; et al. (2025)
Nature Medicine
There is limited evidence supporting the feasibility of using omics and functional technologies to inform treatment decisions. Here we present results from a cohort of 116 melanoma patients in the prospective, multicentric observational Tumor Profiler (TuPro) precision oncology project. Nine independent technologies, mostly at single-cell level, were used to analyze 126 patient samples, generating up to 500 Gb of data per sample (40,000 potential markers) within 4 weeks. Among established and experimental markers, the molecular tumor board selected 54 to inform its treatment recommendations. In 75% of cases, TuPro-based data were judged to be useful in informing recommendations. Patients received either standard of care (SOC) treatments or highly individualized, polybiomarker-driven treatments (beyond SOC). The objective response rate in difficult-to-treat palliative, beyond SOC patients (n = 37) was 38%, with a disease control rate of 54%. Progression-free survival of patients with TuPro-informed therapy decisions was 6.04 months, (95% confidence interval, 3.75-12.06) and 5.35 months (95% confidence interval, 2.89-12.06) in $\geq$ third therapy lines. The proof-of-concept TuPro project demonstrated the feasibility and relevance of omics-based tumor profiling to support data-guided clinical decision-making.
SCIM: Universal Single-Cell Matching with Unpaired Feature Sets
Stark, Stefan; Ficek, Joanna; Locatello, Francesco; et al. (2020)
bioRxiv
Motivation Recent technological advances have led to an increase in the production and availability of single-cell data. The ability to integrate a set of multi-technology measurements would allow the identification of biologically or clinically meaningful observations through the unification of the perspectives afforded by each technology. In most cases, however, profiling technologies consume the used cells and thus pairwise correspondences between datasets are lost. Due to the sheer size single-cell datasets can acquire, scalable algorithms that are able to universally match single-cell measurements carried out in one cell to its corresponding sibling in another technology are needed. Results We propose Single-Cell data Integration via Matching (SCIM), a scalable approach to recover such correspondences in two or more technologies. SCIM assumes that cells share a common (low-dimensional) underlying structure and that the underlying cell distribution is approximately constant across technologies. It constructs a technology-invariant latent space using an auto-encoder framework with an adversarial objective. Multi-modal datasets are integrated by pairing cells across technologies using a bipartite matching scheme that operates on the low-dimensional latent representations. We evaluate SCIM on a simulated cellular branching process and show that the cell-to-cell matches derived by SCIM reflect the same pseudotime on the simulated dataset. Moreover, we apply our method to two real-world scenarios, a melanoma tumor sample and a human bone marrow sample, where we pair cells from a scRNA dataset to their sibling cells in a CyTOF dataset achieving 93% and 84% cell-matching accuracy for each one of the samples respectively. Availability https://github.com/ratschlab/scim

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