空间蛋白质组学：技术方法学进展与临床应用转化

doi:10.3760/cma.j.cn441417-20250402-19010

摘要/Abstract

摘要：

蛋白质的时空动态分布与功能调控是生命活动的核心特征，传统蛋白质组学因难以解析亚细胞定位异质性及动态转位事件而面临瓶颈。空间蛋白质组学通过整合高精度质谱、超分辨成像与人工智能算法，构建了多维分析框架，从而充分了解肿瘤、神经退行性疾病等的发生发展机制。本文简述空间蛋白质组学技术进展与临床应用转化。

关键词:

蛋白质组学, 空间蛋白质组学, 质谱, 成像技术, 进展

Abstract:

The spatiotemporal dynamic distribution and functional regulation of proteins represent core features of life activities. Traditional proteomics faces bottlenecks due to its difficulty in resolving subcellular localization heterogeneity and dynamic translocation events. By integrating high-precision mass spectrometry, super-resolution imaging, and artificial intelligence algorithms, spatial proteomics constructs a multidimensional analytical framework, enabling a comprehensive understanding of the mechanisms underlying the occurrence and development of diseases such as cancer and neurodegenerative disorders. This paper briefly reviews the technological advancements and clinical translational applications of spatial proteomics.

Key words:

Proteomics, Spatial proteomics, Mass spectrometry, Imaging technology, Progress

何东浩尹良红.

空间蛋白质组学：技术方法学进展与临床应用转化 [J]. 国际医药卫生导报, 2025, 31(19): 3218-3222.

He Donghao, Yin Lianghong.

Spatial proteomics: technological methodological advances and clinical application translation [J]. International Medicine and Health Guidance News, 2025, 31(19): 3218-3222.

参考文献

[1] Luo Y, Na Z, Slavoff SA. P-bodies: composition, properties, and functions[J]. Biochemistry, 2018,57(17):2424-2431. DOI: 10.1021/acs.biochem.7b01162.
[2] Rabouille C, Alberti S. Cell adaptation upon stress: the emerging role of membrane-less compartments[J]. Curr Opin Cell Biol, 2017,47:34-42. DOI: 10.1016/j.ceb.2017.02.006.
[3] Wheeler RJ, Hyman AA. Controlling compartmentalization by non-membrane-bound organelles[J]. Philos Trans R Soc Lond B Biol Sci, 2018, 373(1747):20170193. DOI: 10.1098/rstb.2017.0193.
[4] Zhukov A, Popov V. Eukaryotic cell membranes: structure, composition, research methods and computational modelling[J]. Int J Mol Sci, 2023,24(13):11226. DOI: 10.3390/ijms241311226.
[5] Altelaar AF, Munoz J, Heck AJ. Next-generation proteomics: towards an integrative view of proteome dynamics[J]. Nat Rev Genet, 2013,14(1):35-48. DOI: 10.1038/nrg3356.
[6] Cupp-Sutton KA, Wu S. High-throughput quantitative top-down proteomics[J]. Mol Omics, 2020,16(2):91-99. DOI: 10.1039/c9mo00154a.
[7] 潘艳艳,孙永超,张洪霞,等. 儿童原发性肾病综合征激素敏感与耐药者尿蛋白质组学的研究[J]. 国际医药卫生导报,2019,25(15):2420-2421. DOI:10.3760/cma.j.issn.1007-1245.2019.15.004.
[8] Zhang Y, Fonslow BR, Shan B, et al. Protein analysis by shotgun/bottom-up proteomics[J]. Chem Rev, 2013,113(4):2343-2394. DOI: 10.1021/cr3003533.
[9] Aebersold R, Mann M. Mass-spectrometric exploration of proteome structure and function[J]. Nature, 2016,537(7620):347-355. DOI: 10.1038/nature19949.
[10] Cui M, Cheng C, Zhang L. High-throughput proteomics: a methodological mini-review[J]. Lab Invest, 2022,102(11):1170-1181. DOI: 10.1038/s41374-022-00830-7.
[11] Sidoli S, Garcia BA. Middle-down proteomics: a still unexploited resource for chromatin biology[J]. Expert Rev Proteomics, 2017, 14(7):617-626. DOI: 10.1080/14789450.2017.1345632.
[12] Gygi SP, Corthals GL, Zhang Y, et al. Evaluation of two-dimensional gel electrophoresis-based proteome analysis technology[J]. Proc Natl Acad Sci U S A, 2000, 97(17):9390-9395. DOI: 10.1073/pnas.160270797.
[13] Michelsen U, von Hagen J. Isolation of subcellular organelles and structures[J]. Methods Enzymol, 2009,463:305-328. DOI: 10.1016/S0076-6879(09)63019-6.
[14] Qin S, Zhang Y, Tian Y, et al. Subcellular metabolomics: isolation, measurement, and applications[J]. J Pharm Biomed Anal, 2022,210:114557. DOI: 10.1016/j.jpba.2021.114557.
[15] Andersen JS, Mann M. Organellar proteomics: turning inventories into insights[J]. EMBO Rep, 2006, 7(9):874-879. DOI: 10.1038/sj.embor.7400780.
[16] Foster LJ, de Hoog CL, Zhang Y, et al. A mammalian organelle map by protein correlation profiling[J]. Cell, 2006,125(1):187-199. DOI: 10.1016/j.cell.2006.03.022.
[17] Wildgruber R, Weber G, Wise P, et al. Free-flow electrophoresis in proteome sample preparation[J]. Proteomics, 2014,14(4-5):629-636. DOI: 10.1002/pmic.201300253.
[18] Nott A, Schlachetzki JCM, Fixsen BR, et al. Nuclei isolation of multiple brain cell types for omics interrogation[J]. Nat Protoc, 2021, 16(3):1629-1646. DOI: 10.1038/s41596-020-00472-3.
[19] Thimiri Govinda Raj DB, Khan NA, Venkatachalam S, et al. Step-by-step protocol for superparamagnetic nanoparticle-based endosome and lysosome isolation from eukaryotic cell[J]. Methods Mol Biol, 2020, 2125:167-172. DOI: 10.1007/7651_2019_212.
[20] Low TY, Syafruddin SE, Mohtar MA, et al. Recent progress in mass spectrometry-based strategies for elucidating protein-protein interactions[J]. Cell Mol Life Sci, 2021,78(13):5325-5339. DOI: 10.1007/s00018-021-03856-0.
[21] Entzminger KC, Hyun JM, Pantazes RJ, et al. De novo design of antibody complementarity determining regions binding a FLAG tetra-peptide[J]. Sci Rep, 2017, 7(1):10295. DOI: 10.1038/s41598-017-10737-9.
[22] Green N, Alexander H, Olson A, et al. Immunogenic structure of the influenza virus hemagglutinin[J]. Cell, 1982, 28(3):477-487. DOI: 10.1016/0092-8674(82)90202-1.
[23] Lee CM, Adamchek C, Feke A, et al. Mapping protein-protein interactions using affinity purification and mass spectrometry[J]. Methods Mol Biol, 2017, 1610:231-249. DOI: 10.1007/978-1-4939-7003-2_15.
[24] Roux KJ, Kim DI, Burke B. BioID: a screen for protein-protein interactions[J]. Curr Protoc Protein Sci, 2013,74:19.23.1-19.23.14. DOI: 10.1002/0471140864.ps1923s74.
[25] Kalocsay M. APEX Peroxidase-catalyzed proximity labeling and multiplexed quantitative proteomics[J]. Methods Mol Biol, 2019,2008:41-55. DOI: 10.1007/978-1-4939-9537-0_4.
[26] Rhee HW, Zou P, Udeshi ND, et al. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging[J]. Science, 2013, 339(6125):1328-1331. DOI: 10.1126/science.1230593.
[27] Chen CL, Hu Y, Udeshi ND, et al. Proteomic mapping in live Drosophila tissues using an engineered ascorbate peroxidase[J]. Proc Natl Acad Sci U S A, 2015, 112(39):12093-12098. DOI: 10.1073/pnas.1515623112.
[28] Roux KJ, Kim DI, Raida M, et al. A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells[J]. J Cell Biol, 2012, 196(6):801-810. DOI: 10.1083/jcb.201112098.
[29] Kushner J, Papa A, Marx SO. Use of proximity labeling in cardiovascular research[J]. JACC Basic Transl Sci, 2021, 6(7):598-609. DOI: 10.1016/j.jacbts.2021.01.005.
[30] Yang J, Wagner SA, Beli P. Illuminating spatial and temporal organization of protein interaction networks by mass spectrometry-based proteomics[J]. Front Genet, 2015, 6:344. DOI: 10.3389/fgene.2015.00344.
[31] Morawska LP, Hernandez-Valdes JA, Kuipers OP. Diversity of bet-hedging strategies in microbial communities-recent cases and insights[J]. WIREs Mech Dis, 2022, 14(2):e1544. DOI: 10.1002/wsbm.1544.
[32] Meeks JC, Campbell EL, Summers ML, et al. Cellular differentiation in the cyanobacterium Nostoc punctiforme[J]. Arch Microbiol, 2002, 178(6):395-403. DOI: 10.1007/s00203-002-0476-5.
[33] Shaffer SM, Dunagin MC, Torborg SR, et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance[J]. Nature, 2017, 546(7658):431-435. DOI: 10.1038/nature22794.
[34] de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth[J]. Cancer Cell, 2023, 41(3):374-403. DOI: 10.1016/j.ccell.2023.02.016.
[35] Mattiazzi Usaj M, Yeung CHL, Friesen H, et al. Single-cell image analysis to explore cell-to-cell heterogeneity in isogenic populations[J]. Cell Syst, 2021, 12(6):608-621. DOI: 10.1016/j.cels.2021.05.010.
[36] Hickey JW, Neumann EK, Radtke AJ, et al. Spatial mapping of protein composition and tissue organization: a primer for multiplexed antibody-based imaging[J]. Nat Methods, 2022, 19(3):284-295. DOI: 10.1038/s41592-021-01316-y.
[37] Black S, Phillips D, Hickey JW, et al. CODEX multiplexed tissue imaging with DNA-conjugated antibodies[J]. Nat Protoc, 2021, 16(8):3802-3835. DOI: 10.1038/s41596-021-00556-8.
[38] Sirerol-Piquer MS, Cebrián-Silla A, Alfaro-Cervelló C, et al. GFP immunogold staining, from light to electron microscopy, in mammalian cells[J]. Micron, 2012, 43(5):589-599. DOI: 10.1016/j.micron.2011.10.008.
[39] Frenkel-Morgenstern M, Cohen AA, Geva-Zatorsky N, et al. Dynamic proteomics: a database for dynamics and localizations of endogenous fluorescently-tagged proteins in living human cells[J]. Nucleic Acids Res, 2010, 38(Database issue):D508-512. DOI: 10.1093/nar/gkp808.
[40] Yamanaka M, Smith NI, Fujita K. Introduction to super-resolution microscopy[J]. Microscopy (Oxf), 2014, 63(3):177-192. DOI: 10.1093/jmicro/dfu007.
[41] Doll SG, Meshkin H, Bryer AJ, et al. Recognition of the TDP-43 nuclear localization signal by importin α1/β[J]. Cell Rep, 2022, 39(13):111007. DOI: 10.1016/j.celrep.2022.111007.
[42] Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype[J]. N Engl J Med. 2005, 352(3):254-266. DOI: 10.1056/NEJMoa041974.
[43] Goncharov AP, Dicusari Elissaiou C, Ben Aharon Farzalla E, et al. Signalling pathways in a nutshell: from pathogenesis to therapeutical implications in prostate cancer[J]. Ann Med, 2025, 57(1):2474175. DOI: 10.1080/07853890.2025.2474175.
[44] Wu L, Lin Y, Song J, et al. TMEM175: a lysosomal ion channel associated with neurological diseases[J]. Neurobiol Dis, 2023,185:106244. DOI: 10.1016/j.nbd.2023.106244.
[45] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies[J]. Cell, 2019, 179(2):312-339. DOI: 10.1016/j.cell.2019.09.001.
[46] Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review[J]. JAMA, 2013, 310(17):1842-1850. DOI: 10.1001/jama.2013.280319.
[47] Duhamel M, Drelich L, Wisztorski M, et al. Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival[J]. Nat Commun, 2022, 13(1):6665. DOI: 10.1038/s41467-022-34208-6.
[48] Tracy TE, Madero-Pérez J, Swaney DL, et al. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration[J]. Cell, 2022, 185(4):712-728. DOI: 10.1016/j.cell.2021.12.041.
[49] Jean Beltran PM, Federspiel JD, Sheng X, et al. Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases[J]. Mol Syst Biol, 2017, 13(3):922. DOI: 10.15252/msb.20167062.
[50] Cook KC, Tsopurashvili E, Needham JM, et al. Restructured membrane contacts rewire organelles for human cytomegalovirus infection[J]. Nat Commun, 2022, 13(1):4720. DOI: 10.1038/s41467-022-32488-6.
[51] Song X, Xiong A, Wu F, et al. Spatial multi-omics revealed the impact of tumor ecosystem heterogeneity on immunotherapy efficacy in patients with advanced non-small cell lung cancer treated with bispecific antibody[J]. J Immunother Cancer, 2023, 11(2):e006234. DOI: 10.1136/jitc-2022-006234.