A5025935369- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- 3D Printing in Biomedical Research
- Cancer Immunotherapy and Biomarkers
- Advanced Proteomics Techniques and Applications
- RNA and protein synthesis mechanisms
- Bioinformatics and Genomic Networks
- Advanced Fluorescence Microscopy Techniques
- Cancer Cells and Metastasis
- Renal and related cancers
- Gene Regulatory Network Analysis
- Ubiquitin and proteasome pathways
- Enzyme Structure and Function
- Genetics, Aging, and Longevity in Model Organisms
- Protein Structure and Dynamics
- Advanced biosensing and bioanalysis techniques
- Gene expression and cancer classification
- Neurogenesis and neuroplasticity mechanisms
- Genomics and Chromatin Dynamics
- RNA Interference and Gene Delivery
- Cellular Mechanics and Interactions
- Biotin and Related Studies
- RNA Research and Splicing
ETH Zurich
2019-2025
University of Zurich
2019-2024
The Nature Conservancy
2012-2018
Scientific Methods (United States)
2018
Howard Hughes Medical Institute
2007
Abstract A holistic understanding of tissue and organ structure function requires the detection molecular constituents in their original three-dimensional (3D) context. Imaging mass cytometry (IMC) enables simultaneous up to 40 antigens transcripts using metal-tagged antibodies but has so far been restricted two-dimensional imaging. Here we report development 3D IMC for multiplexed analysis at single-cell resolution demonstrate utility technology by human breast cancer samples. The resulting...
Cancer-associated fibroblasts (CAFs) are a diverse cell population within the tumour microenvironment, where they have critical effects on evolution and patient prognosis. To define CAF phenotypes, we analyse single-cell RNA sequencing (scRNA-seq) dataset of over 16,000 stromal cells from tumours 14 breast cancer patients, based which functionally annotate nine phenotypes one class pericytes. We validate this classification system in four additional types use highly multiplexed imaging mass...
Abstract Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune blockade prevent or reverse exhausted T cell states, but exhaustion tumors not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry systematically study environments human that either do contain cells, a focus on luminal subtypes. We find the presence PD-1 high exhaustion-like phenotype...
Despite advances in treatment, lung cancer survival rates remain low. A better understanding of the cellular heterogeneity and interplay cancer-associated fibroblasts (CAFs) within tumor microenvironment will support development personalized therapies. We report a spatially resolved single-cell imaging mass cytometry (IMC) analysis CAFs non-small cell cohort 1,070 patients. identify four prognostic patient groups based on 11 CAF phenotypes with distinct spatial distributions show that are...
•Dynamic structural proteomic screens detect functional changes at high resolution•Detect enzyme activity, phosphorylation, and molecular interactions in situ•Generate new hypotheses increase proteomics coverage•Enabled discovery of a regulatory mechanism glucose uptake E. coli Biological processes are regulated by intermolecular chemical modifications that do not affect protein levels, thus escaping detection classical screens. We demonstrate here global readout based on limited...
Coronavirus disease 2019 (COVID-19) manifests with a range of severities, but immune signatures mild and severe are still not fully understood. Here, we use mass cytometry targeted proteomics to profile the innate response patients or COVID-19 healthy individuals. Sampling at different stages allows us reconstruct pseudo-temporal trajectory response. A surge CD169+ monocytes associated an IFN-γ+MCP-2+ signature rapidly follows symptom onset. At later stages, observe persistent inflammatory...
Abstract Chemoproteomics is a key technology to characterize the mode of action drugs, as it directly identifies protein targets bioactive compounds and aids in development optimized small-molecule compounds. Current approaches cannot identify compound also detect interaction surfaces between ligands without prior labeling or modification. To address this limitation, we here develop LiP-Quant, drug target deconvolution pipeline based on limited proteolysis coupled with mass spectrometry that...
Although breast cancer mortality is largely caused by metastasis, clinical decisions are based on analysis of the primary tumor and lymph node involvement but not phenotype disseminated cells. Here, we use multiplex imaging mass cytometry to compare single-cell phenotypes tumors matched metastases in 205 patients. We observe extensive phenotypic variability between metastatic sites that cell frequently deviate from disease subtype. identify spatial organizations cells associated with patient...
Abstract Organisms use organic molecules called osmolytes to adapt environmental conditions. In vitro studies indicate that thermally stabilize proteins, but mechanisms are controversial, and systematic within the cellular milieu lacking. We analyzed Escherichia coli human protein thermal stabilization by in situ across proteome. Using structural proteomics, we probed osmolyte effects on stability, structure aggregation, revealing common also osmolyte- protein-specific effects. All tested...
One goal of precision medicine is to tailor effective treatments patients' specific molecular markers disease. Here, we used mass cytometry characterize the single-cell signaling landscapes 62 breast cancer cell lines and five from healthy tissue. We quantified 34 in each line upon stimulation by growth factor EGF presence or absence kinase inhibitors. These data—on more than 80 million single cells 4,000 conditions—were fit mechanistic network models that provide insight into how process...
The vulval precursor cells (VPCs) of Caenorhabditis elegans are polarized epithelial that adopt a precise pattern fates through regulated activity basolateral LET-23/EGF receptor and apical LIN-12/Notch. During VPC patterning, there is reciprocal modulation endocytosis trafficking both LET-23 LIN-12. We identified sel-2 as negative regulator lin-12/Notch in the VPCs, found SEL-2 homolog two closely related human proteins, neurobeachin (also known BCL8B) LPS-responsive, beige-like anchor...
Protein–small molecule interactions control many cellular processes, such as allosteric regulation of enzyme activity. One method to study protein–small in a complex sample is limited proteolysis–mass spectrometry (LiP-MS). In this approach, small added cell lysate, which then briefly incubated with nonspecific protease. Since binding can locally alter the protease accessibility its target proteins, yields condition-specific cleavage products. The size fragments reduced by secondary...
Abstract Breast cancer is the most commonly diagnosed in women, with distant metastasis being main cause of breast cancer-related deaths. Elucidating changes tumor and immune ecosystems that are associated metastatic disease essential to improve understanding ultimately treatment metastasis. Here, we developed an in-depth, spatially resolved single-cell atlas phenotypic diversity cells primary human tumors matched metastases, using imaging mass cytometry analyze a total 75 unique antibody...
<p>Immune cell phenotypes in PT and metastases. <b>A,</b> Uniform Manifold Approximation Projection for Dimension Reduction (UMAP) visualization of all lymphoid cells from the T-cell panel dataset, colored by type (<i>n</i> = 87 patients). <b>B,</b> Heatmap showing mean expression T-cell–relevant markers across different phenotypic subtypes after graph-based clustering patients; <i>n</i>_cells 91,000). Euclidean distance with average...
<p>Overview of the clinical cohort and project workflow. <b>A,</b> Overview experimental The study includes primary breast cancer tissue samples with metastases to four different sites (bone, brain, liver, soft tissue). Three antibody panels were used for IMC on consecutive slides, targeting tumor immune phenotypes. <b>B,</b> Targets three their associated function. <b>C,</b> Proportion indicated cell types per patient in after first graph-based...
<p>Phenotypic composition of tumor cells from PT and distant metastasis. <b>A,</b> Left, heatmap showing the median expression level for each cell cluster after flowSOM clustering. Markers used clustering are on <i>x-</i>axis, clusters <i>y-</i>axis. For clustering, all were pooled across samples (<i>n</i> = 87 patients, 559,953 cells), counts in shown (bar plot, gray). Euclidean distance with Ward-D2 linkage was hierarchical rows. Right,...