Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories DOI Creative Commons
Corinna Friedrich, Simon Schallenberg, Marieluise Kirchner

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 11, 2021

Abstract Formalin-fixed paraffin-embedded (FFPE) tissues are a valuable resource for retrospective clinical studies. Here, we evaluate the feasibility of (phospho-)proteomics on FFPE lung tissue regarding protein extraction, quantification, pre-analytics, and sample size. After comparing extraction protocols, use best-performing protocol acquisition deep (phospho-)proteomes from squamous cell adenocarcinoma with >8,000 quantified proteins >14,000 phosphosites tandem mass tag (TMT) approach. With microscaled approach, quantify 7,000 phosphosites, enabling analysis biopsies limited amounts. We also investigate influence pre-analytical variables including fixation time heat-assisted de-crosslinking efficiency proteome coverage. Our improved workflows provide quantitative information abundance phosphosite regulation most relevant oncogenes, tumor suppressors, signaling pathways in cancer. Finally, present general guidelines to which methods best suited different applications, highlighting TMT comprehensive (phospho-)proteome profiling focused studies label-free large cohorts.

Language: Английский

Patient-specific Boolean models of signalling networks guide personalised treatments DOI Creative Commons
Arnau Montagud, Jonas Béal, Luis Tobalina

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Feb. 15, 2022

Prostate cancer is the second most occurring in men worldwide. To better understand mechanisms of tumorigenesis and possible treatment responses, we developed a mathematical model prostate which considers major signalling pathways known to be deregulated. We personalised this Boolean molecular data reflect heterogeneity specific response perturbations patients. A total 488 samples were used build patient-specific models compared available clinical data. Additionally, eight cell line-specific built validate our approach with dose-response several drugs. The effects single combined drugs tested these under different growth conditions. identified 15 actionable points interventions one whose inactivation hinders tumorigenesis. results, nine small molecule inhibitors five those putative targets found dose-dependent effect on four them, notably targeting HSP90 PI3K. These results highlight predictive power illustrate how they can for precision oncology.

Language: Английский

Citations

73
Proteogenomic Markers of Chemotherapy Resistance and Response in Triple-Negative Breast Cancer DOI Creative Commons
Meenakshi Anurag, Eric J. Jaehnig, Karsten Krug

et al.

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(11), P. 2586 - 2605

Published: Aug. 24, 2022

Abstract Microscaled proteogenomics was deployed to probe the molecular basis for differential response neoadjuvant carboplatin and docetaxel combination chemotherapy triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, fatty acid metabolism, that were associated with resistance. Both proteomics transcriptomics sensitivity marked by elevation DNA repair, E2F targets, G2–M checkpoint, interferon-gamma signaling, immune-checkpoint components. Proteogenomic somatic copy-number aberrations identified a resistance-associated 19q13.31–33 deletion where LIG1, POLD1, XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene and/or low mRNA expression levels lack pathologic complete response, higher chromosomal instability index (CIN), poor prognosis in TNBC, as well carboplatin-selective resistance TNBC preclinical models. Hemizygous loss also CIN other types, demonstrating broader clinical implications. Significance: analysis tumors complex landscape associations, encoding genes serving lagging-strand synthesis (LIG1, XRCC1), correlate resistance, and, pan-cancer studies, CIN. This article is highlighted Issue feature, p. 2483

Language: Английский

Citations

73
Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies DOI Creative Commons
Qian Liu, Jing Zhang, Chenchen Guo

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(1), P. 184 - 203.e28

Published: Jan. 1, 2024

Language: Английский

Citations

73
Large-scale production of human blastoids amenable to modeling blastocyst development and maternal-fetal cross talk DOI Creative Commons

Leqian Yu,

Deirdre M. Logsdon,

Carlos A. Pinzón-Arteaga

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(9), P. 1246 - 1261.e9

Published: Sept. 1, 2023

Recent advances in human blastoids have opened new avenues for modeling early development and implantation. One limitation of our first protocol blastoid generation was relatively low efficiency. We now report an optimized the efficient large quantities high-fidelity from naive pluripotent stem cells. This enabled proteomics analysis that identified phosphosite-specific signatures potentially involved derivation and/or maintenance signaling states blastoids. Additionally, we uncovered endometrial stromal effects promoting trophoblast cell survival, proliferation, syncytialization during co-culture with blastocysts. Side-by-side single-cell RNA sequencing revealed similarities differences transcriptome profiles between pre-implantation blastocysts, as well post-implantation cultures, a population resembling migratory trophoblasts Our will facilitate broader use accessible, perturbable, scalable, tractable model

Language: Английский

Citations

51
Pan-cancer proteogenomics expands the landscape of therapeutic targets DOI Creative Commons
Sara R. Savage, Xinpei Yi, Jonathan T. Lei

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(16), P. 4389 - 4407.e15

Published: June 24, 2024

Fewer than 200 proteins are targeted by cancer drugs approved the Food and Drug Administration (FDA). We integrate Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomics data from 1,043 patients across 10 types with additional public datasets to identify potential therapeutic targets. Pan-cancer analysis of 2,863 druggable reveals a wide abundance range identifies biological factors that affect mRNA-protein correlation. Integration proteomic tumors genetic screen cell lines protein overexpression- or hyperactivation-driven dependencies, enabling accurate predictions effective drug Proteogenomic identification synthetic lethality provides strategy target tumor suppressor gene loss. Combining proteogenomic MHC binding prediction prioritizes mutant KRAS peptides as promising neoantigens. Computational shared tumor-associated antigens followed experimental confirmation nominates immunotherapy These analyses, summarized at https://targets.linkedomics.org, form comprehensive landscape peptide targets for companion diagnostics, repurposing, therapy development.

Language: Английский

Citations

28
Spatial proteomics identifies JAKi as treatment for a lethal skin disease DOI Creative Commons
Thierry M. Nordmann, Holly Anderton, Akito Hasegawa

et al.

Nature, Journal Year: 2024, Volume and Issue: 635(8040), P. 1001 - 1009

Published: Oct. 16, 2024

Abstract Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and an emerging public health issue 1–3 . Patients with TEN undergo severe sudden detachment caused keratinocyte cell death. Although molecular mechanisms that drive death have been proposed, the main drivers remain unknown, there no effective therapy for 4–6 Here, to systematically map changes are associated identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics 7,8 We analysed formalin-fixed, paraffin-embedded archived tissue biopsies of three types cutaneous drug reactions varying severity quantified more than 5,000 proteins in keratinocytes skin-infiltrating immune cells. This revealed marked enrichment type I II interferon signatures compartment patients TEN, as well phosphorylated STAT1 activation. Targeted inhibition pan-JAK inhibitor tofacitinib vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration tofacitinib, baricitinib or JAK1-specific inhibitors abrocitinib upadacitinib ameliorated clinical histological disease two distinct mouse models TEN. Crucially, treatment JAK (JAKi) was safe rapid re-epithelialization recovery seven study uncovers JAK/STAT signalling pathways key pathogenic demonstrates targeted JAKi curative therapy.

Language: Английский

Citations

25
The mitochondrial multi-omic response to exercise training across rat tissues DOI Creative Commons
David Amar, Nicole R. Gay, David Jimenez‐Morales

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(6), P. 1411 - 1429.e10

Published: May 2, 2024

Language: Английский

Citations

22
Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer DOI
Jennifer E. Klomp, J. Nathaniel Diehl, Jeffrey A. Klomp

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6700)

Published: June 6, 2024

To delineate the mechanisms by which ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We that share near-identical signaling transforming outputs KRAS-regulated is driven nearly completely ERK. identified 4666 phosphosites on 2123 proteins, of 79 66%, respectively, were not previously associated with ERK, substantially expanding depth breadth phosphorylation events revealing a considerably more complex function for ERK established controls highly dynamic converges cyclin-dependent kinase regulation RAS homolog guanosine triphosphatase (RHO GTPase). Our findings establish most comprehensive molecular portrait drives KRAS-dependent growth.

Language: Английский

Citations

21
Analysis and Visualization of Quantitative Proteomics Data Using FragPipe-Analyst DOI

Yi Hsiao,

Haijian Zhang, Ginny Xiaohe Li

et al.

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

The FragPipe computational proteomics platform is gaining widespread popularity among the research community because of its fast processing speed and user-friendly graphical interface. Although produces well-formatted output tables that are ready for analysis, there still a need an easy-to-use downstream statistical analysis visualization tool. FragPipe-Analyst addresses this by providing R shiny web server to assist users in conducting analyses resulting quantitative data. It supports major quantification workflows, including label-free quantification, tandem mass tags, data-independent acquisition. offers range useful functionalities, such as various missing value imputation options, data quality control, unsupervised clustering, differential expression (DE) using Limma, gene ontology pathway enrichment Enrichr. To support advanced customized visualizations, we also developed FragPipeAnalystR, package encompassing all functionalities extended site-specific post-translational modifications (PTMs). FragPipeAnalystR both open-source freely available.

Language: Английский

Citations

17
PTMNavigator: interactive visualization of differentially regulated post-translational modifications in cellular signaling pathways DOI Creative Commons
Julian Müller, Florian Bayer, Mathias Wilhelm

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 8, 2025

Abstract Post-translational modifications (PTMs) play pivotal roles in regulating cellular signaling, fine-tuning protein function, and orchestrating complex biological processes. Despite their importance, the lack of comprehensive tools for studying PTMs from a pathway-centric perspective has limited our ability to understand how modulate pathways on molecular level. Here, we present PTMNavigator, tool integrated into ProteomicsDB platform that offers an interactive interface researchers overlay experimental PTM data with pathway diagrams. PTMNavigator provides ~3000 canonical manually curated databases, enabling users modify create custom diagrams tailored data. Additionally, automatically runs kinase enrichment algorithms whose results are directly visualization. This view intricate relationship between signaling pathways. We demonstrate utility by applying it two phosphoproteomics datasets, showing can enhance analysis, visualize drug treatments result discernable flow PTM-driven aid proposing extensions existing By enhancing understanding dynamics facilitating discovery PTM-pathway interactions, advances knowledge biology its implications health disease.

Language: Английский

Citations

2