2023-08-14 ワシントン大学セントルイス校
◆さまざまながんタイプでタンパク質を分析し、特定のタンパク質の働きを阻害する治療法や、がん細胞が作成する異常なタンパク質に対する免疫反応を促進する治療法の開発が期待されます。研究は、がんの成長を推進するキータンパク質とその調節メカニズムを明らかにすることを目指しています。
<関連情報>
- https://source.wustl.edu/2023/08/scientists-reveal-how-proteins-drive-growth-of-multiple-cancer-types/
- https://www.cell.com/cell/fulltext/S0092-8674(23)00780-8
- https://www.cell.com/cell/fulltext/S0092-8674(23)00781-X
- https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00253-2
- https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00219-2
汎癌プロテオゲノミクスが癌原性ドライバーと機能状態を結びつける Pan-cancer proteogenomics connects oncogenic drivers to functional states
Yize Li,Eduard Porta-Pardo,Collin Tokheim,Matthew H. Bailey,Tomer M. Yaron,Vasileios Stathias,Yifat Geffen,Kathleen J. Imbach,Song Cao,Shankara Anand,Yo Akiyama,Wenke Liu,Matthew A. Wyczalkowski,Yizhe Song,Erik P. Storrs,Michael C. Wendl,Wubing Zhang,Mustafa Sibai,Victoria Ruiz-Serra,Wen-Wei Liang,Nadezhda V. Terekhanova,Fernanda Martins Rodrigues,Karl R. Clauser,David I. Heiman,Qing Zhang,Francois Aguet,Anna P. Calinawan,Saravana M. Dhanasekaran,Chet Birger,Shankha Satpathy,Daniel Cui Zhou,Liang-Bo Wang,Jessika Baral,Jared L. Johnson,Emily M. Huntsman,Pietro Pugliese,Antonio Colaprico,Antonio Iavarone,Milan G. Chheda,Christopher J. Ricketts,David Fenyö,Samuel H. Payne,Henry Rodriguez,Ana I. Robles,Michael A. Gillette,Chandan Kumar-Sinha,Alexander J. Lazar,Lewis C. Cantley,Gad Getz,Li Ding ,Clinical Proteomic Tumor Analysis Consortium
Cell Published:August 14, 2023
DOI:https://doi.org/10.1016/j.cell.2023.07.014
Highlights
•Multi-omic clusters reveal shared oncogenic driver pathways across ten cancer types
•Genetic changes correlate with altered, tumor-specific protein-protein interactions
•cis/trans-effects and kinase activities show driver heterogeneity and druggability
•Proteomic integration with genomic drivers resolves distinct cancer hallmark patterns
Summary
Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.
翻訳後修飾の汎がん解析により、タンパク質制御の共通パターンが明らかになる Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation
Yifat Geffen,Shankara Anand,Yo Akiyama,Tomer M. Yaron,Yizhe Song,Jared L. Johnson,Akshay Govindan,Özgün Babur,Yize Li,Emily Huntsman,Liang-Bo Wang,Chet Birger,David I. Heiman,Qing Zhang,Mendy Miller,Yosef E. Maruvka,Nicholas J. Haradhvala,Anna Calinawan,Saveliy Belkin,Alexander Kerelsky,Karl R. Clauser,Karsten Krug,Shankha Satpathy,Samuel H. Payne,D.R. Mani,Michael A. Gillette,Saravana M. Dhanasekaran,Mathangi Thiagarajan,Mehdi Mesri,Henry Rodriguez,Ana I. Robles,Steven A. Carr,Alexander J. Lazar,François Aguet,Lewis C. Cantley,Li Ding,Gad Getz,Clinical Proteomic Tumor Analysis Consortium
Cell Published:August 14, 2023
DOI:https://doi.org/10.1016/j.cell.2023.07.013
Highlights
•Unsupervised clustering reveals 33 pan-cancer multi-omic signatures
•PTM dysregulation is associated with distinct DNA damage repair mechanisms
•Changes in acetylation of metabolic proteins correlate with tumor immune state
•Phosphorylation of Thr/Ser kinases is affected by proximal acetylation
Summary
Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.
統合的なマルチオミクスがんプロファイリングにより、治療の脆弱性と起源細胞に関連するDNAメチル化パターンが明らかになる Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin
Wen-Wei Liang,Rita Jui-Hsien Lu,Reyka G. Jayasinghe,Steven M. Foltz,Eduard Porta-Pardo,Yifat Geffen,Michael C. Wendl,Rossana Lazcano,Iga Kolodziejczak,Yizhe Song,Akshay Govindan,Elizabeth G. Demicco,Xiang Li,Yize Li,Sunantha Sethuraman,Samuel H. Payne,David Fenyö,Henry Rodriguez,Maciej Wiznerowicz,Hui Shen,D.R. Mani,Karin D. Rodland,Alexander J. Lazar,Ana I. Robles,Li Ding,Clinical Proteomic Tumor Analysis Consortium
Cancer Cell Published:August 14, 2023
DOI:https://doi.org/10.1016/j.ccell.2023.07.013
Highlights
•Pan-cancer epigenetic aberrations and their transcriptional and translational changes
•FGFR2 and EGFR hypomethylation are bona fide driver DNA methylation events
•STAT5A methylation is a potential switch for immunosuppression in squamous tumors
•Methylation subtypes illuminate cell origin, tumor heterogeneity, and tumor phenotype
Summary
DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor’s epigenetic landscape and the role of its cell-of-origin.
汎癌解析のためのプロテオゲノムデータとリソース Proteogenomic data and resources for pan-cancer analysis
Yize Li,Yongchao Dou,Felipe Da Veiga Leprevost,Yifat Geffen,Anna P. Calinawan,François Aguet,Yo Akiyama,Shankara Anand,Chet Birger,Song Cao,Rekha Chaudhary,Padmini Chilappagari,Marcin Cieslik,Antonio Colaprico,Daniel Cui Zhou,Corbin Day,Marcin J. Domagalski,Myvizhi Esai Selvan,David Fenyö,Steven M. Foltz,Alicia Francis,Tania Gonzalez-Robles,Zeynep H. Gümüş,David Heiman,Michael Holck,Runyu Hong,Yingwei Hu,Eric J. Jaehnig,Jiayi Ji,Wen Jiang,Lizabeth Katsnelson,Karen A. Ketchum,Robert J. Klein,Jonathan T. Lei,Wen-Wei Liang,Yuxing Liao,Caleb M. Lindgren,Weiping Ma,Lei Ma,Michael J. MacCoss,Fernanda Martins Rodrigues,Wilson McKerrow,Ngoc Nguyen,Robert Oldroyd,Alexander Pilozzi,Pietro Pugliese,Boris Reva,Paul Rudnick,Kelly V. Ruggles,Dmitry Rykunov,Sara R. Savage,Michael Schnaubelt,Tobias Schraink,Zhiao Shi,Deepak Singhal,Xiaoyu Song,Erik Storrs,Nadezhda V. Terekhanova,Ratna R. Thangudu,Mathangi Thiagarajan,Liang-Bo Wang,Joshua M. Wang,Ying Wang,Bo Wen,Yige Wu,Matthew A. Wyczalkowski,Yi Xin,Lijun Yao,Xinpei Yi,Hui Zhang,Qing Zhang,Maya Zuhl,Gad Getz,Li Ding,Alexey I. Nesvizhskii,Pei Wang,Ana I. Robles,Bing Zhang,Samuel H. Payne,Clinical Proteomic Tumor Analysis Consortium
Cancer Cell Published:August 14, 2023
DOI:https://doi.org/10.1016/j.ccell.2023.06.009
Summary
The National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry proteomics data.
