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

WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs DOI Creative Commons
Yuxing Liao, Jing Wang, Eric J. Jaehnig

et al.

Nucleic Acids Research, Journal Year: 2019, Volume and Issue: 47(W1), P. W199 - W205

Published: May 2, 2019

Abstract WebGestalt is a popular tool for the interpretation of gene lists derived from large scale -omics studies. In 2019 update, supports 12 organisms, 342 identifiers and 155 175 functional categories, as well user-uploaded databases. To address growing unique need phosphoproteomics data interpretation, we have implemented phosphosite set analysis to identify important kinases data. We completely redesigned result visualizations user interfaces improve user-friendliness provide multiple types interactive publication-ready figures. facilitate comprehension enrichment results, two methods reduce redundancy between enriched sets. introduced web API other applications get programmatically server or pass analysis. also wrapped core computation into an R package called WebGestaltR users perform locally in third party workflows. can be freely accessed at http://www.webgestalt.org.

Language: Английский

Citations

2804
Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma DOI Creative Commons
Michael A. Gillette, Shankha Satpathy, Song Cao

et al.

Cell, Journal Year: 2020, Volume and Issue: 182(1), P. 200 - 225.e35

Published: July 1, 2020

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization 110 tumors 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, gender. Proteomic phosphoproteomic data illuminated downstream copy number aberrations, somatic fusions identified vulnerabilities associated with events involving KRAS, EGFR, ALK. Immune subtyping a complex landscape, reinforced association STK11 immune-cold behavior, underscored potential immunosuppressive role neutrophil degranulation. Smoking-associated LUADs showed correlation other environmental exposure signatures field effect in NATs. Matched NATs allowed identification differentially expressed proteins diagnostic utility. This proteogenomics dataset represents unique public resource for researchers clinicians seeking to better understand treat adenocarcinomas.

Language: Английский

Citations

587
Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy DOI Creative Commons
Karsten Krug, Eric J. Jaehnig, Shankha Satpathy

et al.

Cell, Journal Year: 2020, Volume and Issue: 183(5), P. 1436 - 1456.e31

Published: Nov. 1, 2020

The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued preserve post-translational modifications, including protein phosphorylation acetylation. Proteogenomics challenged standard cancer diagnoses, provided detailed analysis the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, allowed accurate assessment Rb status for prediction CDK4/6 inhibitor responsiveness. Phosphoproteomics uncovered novel associations between suppressor loss targetable kinases. Acetylproteome highlighted acetylation on key nuclear proteins involved in damage response revealed cross-talk cytoplasmic mitochondrial metabolism. Our results underscore potential proteogenomics clinical investigation through annotation pathways biological features remarkably heterogeneous malignancy.

Language: Английский

Citations

402
Proteogenomic characterization of pancreatic ductal adenocarcinoma DOI Creative Commons

Liwei Cao,

Chen Huang, Daniel Cui Zhou

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(19), P. 5031 - 5052.e26

Published: Sept. 1, 2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 tissues. Proteomic, phosphoproteomic, glycoproteomic analyses were used to characterize proteins their modifications. In addition, whole-genome sequencing, whole-exome methylation, RNA sequencing (RNA-seq), microRNA (miRNA-seq) performed on same tissues facilitate an integrated determine impact genomic protein expression, signaling pathways, post-translational To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using features verified pathological estimation based histological review. This characterization will serve as valuable resource for community, paving way early detection identification novel therapeutic targets.

Language: Английский

Citations

378
A proteogenomic portrait of lung squamous cell carcinoma DOI Creative Commons
Shankha Satpathy, Karsten Krug, Pierre M. Jean Beltran

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(16), P. 4348 - 4371.e40

Published: Aug. 1, 2021

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape LSCC, providing deeper exposition LSCC biology potential implications. identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 overexpressing target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such LSD1 EZH2 to SOX2-overexpressing tumors. Our data support complex regulation metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related observations suggest directions further investigation. Proteogenomic dissection CDKN2A mutations argue more nuanced assessment RB1 protein expression phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation LUAD, HNSCC identified both unique common vulnerabilities. These proteogenomics resources may guide research into treatment LSCC.

Language: Английский

Citations

278
Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors DOI Creative Commons
Lizhi He, Jhih-Hua Jhong, Qi Chen

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 37(5), P. 109955 - 109955

Published: Nov. 1, 2021

Macrophages undergoing M1- versus M2-type polarization differ significantly in their cell metabolism and cellular functions. Here, global quantitative time-course proteomics phosphoproteomics paired with transcriptomics provide a comprehensive characterization of temporal changes metabolism, functions, signaling pathways that occur during the induction phase polarization. Significant differences in, especially, metabolic are observed, including glucose glycosaminoglycan retinoic acid signaling. Kinase-enrichment analysis shows activation patterns specific kinases distinct inhibitor drug screens identify drugs selectively block M2- but not M1-type polarization, mitogen-activated protein kinase (MEK) histone deacetylase (HDAC) inhibitors. These datasets resource to critical for macrophage In proof-of-principle approach, we use these show MEK is required by promoting peroxisome proliferator-activated receptor-γ (PPARγ)-induced

Language: Английский

Citations

196
Application of Proteomics in Cancer: Recent Trends and Approaches for Biomarkers Discovery DOI Creative Commons

Yang Woo Kwon,

Han-Seul Jo,

Sungwon Bae

et al.

Frontiers in Medicine, Journal Year: 2021, Volume and Issue: 8

Published: Sept. 22, 2021

Proteomics has become an important field in molecular sciences, as it provides valuable information on the identity, expression levels, and modification of proteins. For example, cancer proteomics unraveled key mechanistic studies tumor growth metastasis, which contributed to identification clinically applicable biomarkers well therapeutic targets. Several proteome databases have been established are being shared worldwide. Importantly, integration with other omics is providing extensive data related mechanisms target modulators. These may be analyzed processed through bioinformatic pipelines obtain useful information. The purpose this review provide overview recent advances proteomic techniques. In particular, we aim offer insights into current brain cancer, applications a relatively early stage. This covers from discovery characterization technology. Moreover, addresses global trends approaches for translational research. As core method research, continued development expected at scale beyond that previously seen.

Language: Английский

Citations

188
Cancer proteogenomics: current impact and future prospects DOI
D.R. Mani, Karsten Krug, Bing Zhang

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(5), P. 298 - 313

Published: March 2, 2022

Language: Английский

Citations

150
Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness DOI Creative Commons
Yize Li, T. Mamie Lih, Saravana M. Dhanasekaran

et al.

Cancer Cell, Journal Year: 2022, Volume and Issue: 41(1), P. 139 - 163.e17

Published: Dec. 22, 2022

Clear cell renal carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- intratumoral heterogeneity (ITH) results in varying prognosis treatment outcomes. To obtain the comprehensive profile ccRCC, we perform integrative histopathologic, proteogenomic, metabolomic analyses on 305 ccRCC tumor segments 166 paired adjacent normal tissues from 213 cases. Combining histologic molecular profiles reveals ITH 90% ccRCCs, with 50% demonstrating immune signature heterogeneity. High grade, along BAP1 mutation, genome instability, increased hypermethylation, a specific protein glycosylation define high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing adverse sarcomatoid rhabdoid phenotypes uncover gene signatures potential insights into evolution. In vitro line studies confirm inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective strategies.

Language: Английский

Citations

109
Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation DOI Creative Commons
Yifat Geffen, Shankara Anand, Yo Akiyama

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(18), P. 3945 - 3967.e26

Published: Aug. 1, 2023

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology both normal cancer cells. Advances mass spectrometry enable high-throughput, accurate, sensitive measurement of PTM levels to better understand their role, prevalence, crosstalk. Here, we analyze the largest collection proteogenomics data from 1,110 patients with profiles across 11 types (10 National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns changes protein acetylation phosphorylation involved hallmark processes. These revealed subsets tumors, different types, including those dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated immune response acetylation, affected kinase specificity crosstalk between modified histone regulation. Overall, this resource highlights rich biology governed PTMs exposes potential new therapeutic avenues.

Language: Английский

Citations

78