Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(14), P. 9094 - 9138

Published: June 28, 2023

Biomolecular condensates, membrane-less entities arising from liquid–liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated degenerative diseases cancer. This review thoroughly examines the dual nature of biomolecular spotlighting role cancer, particularly concerning p53 tumor suppressor. Given that over half malignant tumors possess mutations TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, not only misfolds but also forms aggregates analogous other protein-based amyloids, thus significantly influencing progression through loss-of-function, negative dominance, gain-of-function pathways. The exact molecular mechanisms underpinning mutant remain elusive. However, cofactors like nucleic acids glycosaminoglycans are known be critical players intersection between diseases. Importantly, we reveal molecules capable inhibiting aggregation curtail proliferation migration. Hence, targeting transitions solid-like amorphous states offers promising direction innovative diagnostics therapeutics.

Language: Английский

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Role of condensates in modulating DNA repair pathways and its implication for chemoresistance

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(6), P. 104800 - 104800

Published: May 9, 2023

For cells, it is important to repair DNA damage, such as double-strand and single-strand breaks, because unrepaired can compromise genetic integrity, potentially leading cell death or cancer. Cells have multiple damage pathways that been the subject of detailed genetic, biochemical, structural studies. Recently, scientific community has started gain evidence breaks may occur within biomolecular condensates also contribute through concentrating genotoxic agents used treat various cancers. Here, we summarize key features note where they implicated in breaks. We describe suggesting be involved other types including nucleotide modifications (e.g., mismatch oxidized bases), bulky lesions, among others. Finally, discuss old new mysteries could now addressed considering properties condensates, chemoresistance mechanisms. Chemical changes highly harmful living organisms. DNA, like molecules, undergo chemical reactions. These reactions spontaneously a result exposure chemicals radiation (1Lindahl T. Instability decay primary structure DNA.Nature. 1993; 362: 709-715Crossref PubMed Scopus (4388) Google Scholar). When these altered structure, base excision block gene expression replication negatively affecting homeostasis, function, survival (2Alhmoud J.F. Woolley Al Moustafa A.E. Malki M.I. damage/repair management cancers.Cancers (Basel). 2020; 121050Crossref (96) Thus, promptly properly repaired by cells allow for organism survival. Decades investigation into shed light on diverse cellular responsible resolve damage. include (BER), (NER), homologous recombination (HR), (MMR), non-homologous end joining (NHEJ) (3Chatterjee N. Walker G.C. Mechanisms repair, mutagenesis.Environ. Mol. Mutagen. 2017; 58: 235-263Crossref (801) Scholar, 4Huang R. Zhou P.K. repair: historical perspectives, mechanistic clinical translation targeted cancer therapy.Signal. Transduct Target. Ther. 2021; 6: 254Crossref (121) Dozens different proteins must efficiently recruited at sites work coordination proper repair. Structure-based studies revealed interacting portions recruitment lesions (5Perry J.J. Cotner-Gohara E. Ellenberger Tainer J.A. Structural dynamics signaling repair.Curr. Opin. Struct. Biol. 2010; 20: 283-294Crossref (41) 6Bigot Day M. Baldock R.A. Watts F.Z. Oliver A.W. Pearl L.H. Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 9-1-1 control G1 checkpoint.Elife. 2019; 8e44353Crossref (23) 7Sun Y. McCorvie T.J. Yates L.A. Zhang X. basis recombination.Cell. Life Sci. 77: 3-18Crossref (54) 8Blackford A.N. Jackson S.P. ATM, ATR, DNA-PK: trinity heart response.Mol. Cell. 66: 801-817Abstract Full Text PDF 9McPherson K.S. Korzhnev D.M. Targeting protein-protein response chemotherapy.RSC Chem. 2: 1167-1195Crossref 10Cleary J.M. Aguirre A.J. Shapiro G.I. D'Andrea A.D. Biomarker-guided development inhibitors.Mol. 78: 1070-1085Abstract (113) Moreover, great emphasis recently put disordered regions molecules shared function subcellular compartments not enclosed membranes, called (11Spegg V. Altmeyer Biomolecular damage: more than just phase.DNA Repair (Amst). 106103179Crossref (25) 12Jiang S. Fagman J.B. Chen C. Alberti Liu B. Protein phase separation its role tumorigenesis.Elife. 9e60264Crossref 13Tong Tang Xu J. Wang W. Zhao Yu et al.Liquid-liquid tumor biology.Signal. Transduct. Target 2022; 7: 221Crossref (9) In this review, focus involvement open questions field condensate properties. A emerging study biology consists identification characterization condensates. Condensates are defined sub-cellular physically membranes concentrate (including nucleic acids) (14Sabari B.R. Dall'Agnese A. Young nucleus.Trends Biochem. 45: 961-977Abstract (148) 15Conti B.A. Oppikofer condensates: opportunities drug discovery RNA therapeutics.Trends Pharmacol. 43: 820-837Abstract Scholar) compartmentalize biochemical 16Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. organizers biochemistry.Nat. Rev. Cell 18: 285-298Crossref (2427) 17Harrison A.F. Shorter RNA-binding prion-like domains health disease.Biochem. 474: 1417-1438Crossref (252) 18Shin Brangwynne C.P. Liquid condensation physiology disease.Science. 357eaaf4382Crossref (1651) The first observed were Nucleolus (19Sirri Urcuqui-Inchima Roussel P. Hernandez-Verdun D. Histochem. 2008; 129: 13-31Crossref (308) Cajal bodies (20Morris G.E. Body.Biochim. Biophys. Acta. 1783: 2108-2115Crossref Thanks advancement microscopy technologies growing interest those compartments, many discovered, transcriptional (21Sabari Boija Klein I.A. Coffey E.L. Shrinivas K. al.Coactivator super-enhancers links control.Science. 2018; 361eaar3958Crossref 22Shrinivas Sabari Zamudio A.V. al.Enhancer drive formation condensates.Mol. 75: 549-561.e547Abstract (193) Scholar), nuclear speckles (23Spector D.L. Lamond A.I. Nuclear speckles.Cold Spring Harb. Perspect. 2011; 3a000646Crossref (539) splicing (24Guo Y.E. Manteiga J.C. Henninger J.E. Hannett N.M. al.Pol II phosphorylation regulates switch between condensates.Nature. 572: 543-548Crossref (317) constitutive heterochromatin (25Keenen M.M. Brown Brennan L.D. Renger Khoo H. Carlson C.R. al.HP1 compact mechanically positionally stable separated domains.Elife. 10e64563Crossref (37) 26Strom A.R. Emelyanov Mir Fyodorov D.V. Darzacq Karpen G.H. Phase drives domain formation.Nature. 547: 241-245Crossref (993) 27Larson A.G. Elnatan Keenen Trnka M.J. Johnston Burlingame A.L. al.Liquid droplet HP1α suggests heterochromatin.Nature. 236-240Crossref (926) stress granules (28Brangwynne Eckmann Courson D.S. Rybarska Hoege Gharakhani al.Germline P liquid droplets localize controlled dissolution/condensation.Science. 2009; 324: 1729-1732Crossref (1614) (29Gao X.K. Rao X.S. Cong X.X. Sheng Z.K. Sun Y.T. S.B. al.Phase insulin receptor substrate 1 insulin/IGF-1 signalosomes.Cell Discov. 8: 60Crossref (5) 30Su Ditlev Hui Xing Banjade Okrut promotes T signal transduction.Science. 2016; 352: 595-599Crossref (625) 31Ditlev Vega Koster Su Tani Lakoduk A.M. al.A composition-dependent molecular clutch actin.Elife. 8e42695Crossref (56) 32Zamudio Afeyan L.K. al.Mediator factors identity genes.Mol. 76: 753-766.e756Abstract (112) 33Jaqaman membrane signaling.Curr. 69: 48-54Crossref (0) 34Case L.B. Regulation transmembrane separation.Annu. 48: 465-494Crossref (139) 35Zeng Guan Wu Tong al.Reconstituted postsynaptic density platform understanding synapse plasticity.Cell. 174: 1172-1187Abstract (211) 36Lin Suen Jeffrey Wieteska L. Stainthorp Seiler al.Receptor tyrosine kinases regulate transduction liquid–liquid state.bioRxiv. ([preprint])https://doi.org/10.1101/783720Crossref 37Huang W.Y.C. Alvarez Kondo Y.K. Chung J.K. Lam H.Y.M. assembly transition kinetic proofreading modulate Ras activation SOS.Science. 363: 1098-1103Crossref 38Zeng Shang Araki Guo Huganir R.L. densities underlies synaptic complexes 166: 1163-1175Abstract (300) 39Dall'Agnese Platt Zheng Friesen G. Blaise al.The dynamic clustering disrupted resistance.Nat. Commun. 13: 7522Crossref (1) pore (40Hampoelz Schwarz Ronchi Bragulat-Teixidor Tischer Gaspar I. al.Nuclear pores assemble from nucleoporin during Oogenesis.Cell. 179: 671-686Abstract (45) miRNA processing (41Lee S.C. Martienssen plant processing.Nat. 23: 5-6Crossref (2) (DDR) 42Kilic Lezaja Gatti Bianco Michelena Imhof determines liquid-like behavior compartments.EMBO 38e101379Crossref (205) 43Vítor A.C. Sridhara Sabino Afonso Grosso Martin R.M. al.Single-molecule imaging transcription damaged chromatin.Sci. Adv. 5eaau1249Crossref (32) 44Capozzo Iannelli F. Francia d'Adda di Fagagna Express repress? dilemma chromatin.FEBS 284: 2133-2147Crossref (22) (Fig. 1). physicochemical suggest functions (45Alberti Gladfelter Mittag Considerations challenges studying liquid-liquid condensates.Cell. 176: 419-434Abstract (1065) fast adaptive responses environment. They buffer concentrations proteins; activate reactions; sequester inactivate their specific viscoelastic properties, generate mechanical forces. act filters, example, nucleopore which permit deny entry nucleus (30Su 45Alberti 46Li C.H. al.MeCP2 neurodevelopmental disease.Nature. 586: 440-444Crossref (77) 47Schmidt H.B. Görlich Transport selectivity pores, separation, membraneless organelles.Trends 41: 46-61Abstract (267) Among physical models explain how formed, one them Liquid-Liquid Separation (LLPS) (48Hyman Weber C.A. Jülicher Liquid-liquid biology.Annu. Dev. 2014; 30: 39-58Crossref LLPS described thermodynamically driven phenomenon consisting de-mixing solution two distinct phases. 1940s, Flory Huggins ability polymers, proteins, self-organize discrete (49Flory P.J. Thermodynamics high polymer solutions.J. Phys. 1941; 9: 423-432Crossref (1278) 50Huggins M.L. Solutions long chain compounds.J. 440Crossref over last 10 years, essential life shown able form dense phases resembling 21Sabari 24Guo 51Henninger Oksuz O. Sagi LeRoy al.RNA-mediated feedback 184: 207-225.e224Abstract (175) 52Chatterjee Maltseva Kan Hosseini Gonella Bonn al.Lipid-driven interfacial ordering FUS.Sci. 8eabm7528Crossref dividing milieu "condensed phase" "dilute 2). Considering potential impact biomedical field, determine what leads generation compartments. Over suggested promoted several factors, protein (51Henninger 53Dignon G.L. Best R.B. Mittal separation: driving forces macroscopic properties.Annu. 71: 53-75Crossref (177) Different known promote formation, structured intrinsically (IDRs)/low complexity (LCDs) play behaviors, IDRs studied disease contexts (54Darling Oldfield C.J. Uversky V.N. Intrinsically proteome human membrane-less organelles.Proteomics. 18e1700193Crossref (119) There IDRs, elastin-like polypeptides (55Muiznieks Sharpe Pomès Keeley F.W. Role elastin extracellular matrix proteins.J. 430: 4741-4753Crossref (57) (56Kim H.J. Kim N.C. Y.D. Scarborough E.A. Moore Diaz Z. al.Mutations hnRNPA2B1 hnRNPA1 cause multisystem proteinopathy ALS.Nature. 2013; 495: 467-473Crossref (1023) enriched charged amino acids (57Miyagi Yamazaki Ueda Narumi Hayamizu Uji I.H. patterning proportion residues arginine-rich mixed-charge organelle protein.Int. 7658Crossref 58Uversky Gillespie J.R. Fink Why "natively unfolded" unstructured under physiologic conditions?.Proteins. 2000; 415-427Crossref Several tried investigate relevance IDR composition formation. seem preferentially partners show similar characteristics behavior, charge–charge hydrophobic (59Lyons Veettil R.T. Pradhan Fornero De La Cruz Ito al.Functional partitioning regulators patterned charge blocks.Cell. 2023; 186: 327-345.e328Abstract importance protein–protein reasonable think would possible artificially design will alter therapeutic purposes. Kameda colleagues designed small peptides either impaired p53 vitro. This approach taken peptide-therapeutics (60Kamagata Ariefai Takahashi Hando Subekti D.R.G. Ikeda al.Rational peptide regulating residue-residue contact energy.Sci. Rep. 1213718Crossref only drivers Indeed, roles promoting (61Ilık İ Aktaş speckles: hubs regulation.FEBS 289: 7234-7245Crossref (28) (62Wheeler Matheny Jain Abrisch Parker Distinct stages granule disassembly.Elife. 5e18413Crossref (409) Notably, there controlling dissolution (63Sharp P.A. Chakraborty A.K. regulation condensates.RNA. 28: 52-57Crossref (13) interact IDRs. One example RNA-mediated model proposed transcribed RNAs, short enhancer-RNA, initially stimulate increasing weak multivalent components appears favor until overall zero (charge-balance model). At point, further both enhancer-RNA pre-mRNA, condensate. subdomains SH3 (64Amaya Ryan V.H. Fawzi N.L. Fyn kinase interacts induces low-complexity hnRNPA2.J. 293: 19522-19531Abstract (27) α-helical (65Conicella Dignon Zerze Schmidt D'Ordine Y.C. al.TDP-43 tunes function.Proc. Natl. Acad. U. 117: 5883-5894Crossref (152) Genomic constantly subjected endogenous environmental threats, oxidative stress, alkylation, UV-damage, chemotherapeutics, so on. threats incorrectly mutations chromosomal rearrangements aberrations. alterations lead genomic instability, pathologies, ranging neurodegenerative diseases (66Postel-Vinay Vanhecke Olaussen K.A. Lord Ashworth Soria exploiting DNA-repair defects optimizing lung treatment.Nat. Clin. Oncol. 2012; 144-155Crossref (89) 67Hanahan Weinberg Hallmarks cancer: next generation.Cell. 144: 646-674Abstract (44586) recognition (or tolerance) lesions. together, an orchestra, playing symphony DDR cell-type-, cell-cycle stage- chromatin context-dependent manner (68Vaddavalli P.L. Schumacher network: systemic aging.Trends Genet. 38: 598-612Abstract 69Jackson Bartek DNA-damage 461: 1071-1078Crossref (3969) 70Polo S.E. Dynamics breaks: modifications.Genes 25: 409-433Crossref (844) 71van Attikum Gasser S.M. Crosstalk histone response.Trends 19: 207-217Abstract (416) 72Yasuhara Zou Impacts compartmentalization repair.DNA 105103162Crossref (4) three main classes pathways. class single level non-distorting BER pathway. pathway repairs majority alkylating damages removal base. It (SSBs) PARP (73Caldecott K.W. break disease.Trends 32: 733-745Abstract 74Saville K.M. Clark Wilk Rogers G.D. Andrews Koczor al.NAD(+)-mediated mammalian 93102930Crossref 75Caldecott Mammalian dancing moonlight.DNA 93102921Crossref second includes NER pathway, repairing distorting deriving adducts UV-induced excising degrading stretch ssDNA containing then restoring correct nucleotides polymerization-dependent (76Apelt Lans Schärer O.D. Luijsterburg M.S. Nucleotide leaves mark chromatin: detection nucleosomes.Cell. 7925-7942Crossref (12) 77Duan Speer Ulibarri K.J. Mao Transcription-coupled insights approaches.DNA 103103126Crossref (11) 78Krasikova Rechkunova Lavrik Neurological Abnormalities.Int. 22: 6220Crossref third MMR, whose polymerase misincorporation errors ensuring highest fidelity process. MMR replacement strand 3). usually originate following: (i) mismatches occurring replication; (ii) minority G, (iii) bulges repeated oligonucleotide sequences, trinucleotide expansion (79Elez Mismatch preserving genome

Language: Английский

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Coacervates Composed of Low‐Molecular‐Weight Compounds– Molecular Design, Stimuli Responsiveness, Confined Reaction

Advanced Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

The discovery of coacervation within living cells through liquid-liquid phase separation has inspired scientists to investigate its fundamental principles and significance. Indeed, coacervates composed low-molecular-weight compounds based on supramolecular strategy can offer valuable models for biomolecular condensates useful tools. This mini-review highlights recent findings advances in (artificial condensates), primarily compounds, with focuses their molecular design, stimuli responsiveness, controlled reactions or leading the coacervates.

Language: Английский

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Deciphering the role of liquid-liquid phase separation in sarcoma: Implications for pathogenesis and treatment

Cancer Letters, Journal Year: 2025, Volume and Issue: 616, P. 217585 - 217585

Published: Feb. 23, 2025

Language: Английский

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SRSF9 mediates oncogenic RNA splicing of SLC37A4 via liquid–liquid phase separation to promote oral cancer progression

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Oral cancer represents a significant proportion of head and neck malignancies, accounting for approximately 3 % all malignant tumors worldwide. Alternative splicing (AS), post-transcriptional regulatory mechanism, is increasingly linked to development. The precise impact AS on oral progression not well understood. Bioinformatics, semi-quantitative RT-PCR, minigene reporter system detect the skipping SLC37A4 exon 7 in cancer. FRAP, live cell immunofluorescence demonstrates that SRSF9 can undergo liquid-liquid phase separation (LLPS). In vivo vitro experiments with subcutaneous graft tumors, CCK8, EdU, transwell, others were used effects its induced SLC37A4-S isoforms phenotype cells. Our investigation revealed multitude aberrant alternative events within tumor tissues, most notably pronounced gene. This anomaly leads production truncated isoform, SLC37A4-S, which associated poor prognosis significantly augments proliferation metastatic potential cells relative wild-type SLC37A4-L. Mechanically, may play role SLC37A4. Furthermore, capable undergoing LLPS, process driven by arginine-serine-rich (RS) domain. Disruption LLPS through use inhibitors or mutants effectively prevents influence Significantly, our research both regulated contribute cisplatin chemotherapy resistance study elucidates mechanism mediates cancer, thereby establishing basis considering as therapeutic targets treatment.

Language: Английский

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The Burgeoning Significance of Liquid-Liquid Phase Separation in the Pathogenesis and Therapeutics of Cancers

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(5), P. 1652 - 1668

Published: Jan. 1, 2024

Liquid-liquid phase separation (LLPS) is a physiological phenomenon that parallels the mixing of oil and water, giving rise to compartments with diverse physical properties.Biomolecular condensates, arising from LLPS, serve as critical regulators gene expression control, particular significance in context malignant tumors.Recent investigations have unveiled intimate connection between LLPS cancer, nexus profoundly impacts various facets cancer progression, including DNA repair, transcriptional regulation, oncogene expression, formation membraneless organelles within microenvironment.This review provides comprehensive account evolution molecular pathological level.We explore mechanisms by through which biomolecular condensates govern cellular processes, encompassing signal transduction, responses environmental stressors.Furthermore, we concentrate on potential therapeutic targets development small-molecule inhibitors associated prevalent clinical malignancies.Understanding role its interplay tumor milieu holds promise for enhancing treatment strategies, particularly overcoming drug resistance challenges.These insights offer innovative perspectives support advancing therapy.

Language: Английский

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Emerging Implications of Phase Separation in Cancer

Advanced Science, Journal Year: 2022, Volume and Issue: 9(31)

Published: Sept. 18, 2022

Abstract In eukaryotic cells, biological activities are executed in distinct cellular compartments or organelles. Canonical organelles with membrane‐bound structures well understood. Cells also inherently contain versatile membrane‐less (MLOs) that feature liquid gel‐like bodies. A biophysical process termed liquid–liquid phase separation (LLPS) elucidates how MLOs form through dynamic biomolecule assembly. LLPS‐related molecules often have multivalency, which is essential for low‐affinity inter‐ intra‐molecule interactions to trigger separation. Accumulating evidence shows LLPS concentrates and organizes desired segregates unneeded cells. Thus, tunable functional specificity response environmental stimuli metabolic processes. Aberrant widely associated several hallmarks of cancer, including sustained proliferative signaling, growth suppressor evasion, cell death resistance, telomere maintenance, DNA damage repair, etc. Insights into the molecular mechanisms provide new insights cancer therapeutics. Here, current understanding emerging concepts its involvement comprehensively reviewed.

Language: Английский

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Phase separation in cancer at a glance

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: April 1, 2023

Abstract Eukaryotic cells are segmented into multiple compartments or organelles within the cell that regulate distinct chemical and biological processes. Membrane-less membrane-less microscopic cellular contain protein RNA molecules perform a wide range of functions. Liquid–liquid phase separation (LLPS) can reveal how develop via dynamic biomolecule assembly. LLPS either segregates undesirable from aggregates desired ones in cells. Aberrant results production abnormal biomolecular condensates (BMCs), which cause cancer. Here, we explore intricate mechanisms behind formation BMCs its biophysical properties. Additionally, discuss recent discoveries related to tumorigenesis, including aberrant signaling transduction, stress granule formation, evading growth arrest, genomic instability. We also therapeutic implications Understanding concept mechanism role tumorigenesis is crucial for antitumor strategies.

Language: Английский

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Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 18, 2024

Abstract Once considered unconventional cellular structures, membraneless organelles (MLOs), substructures involved in biological processes or pathways under physiological conditions, have emerged as central players dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, metabolism to cancer, influence on human health disease extends widely. This review discusses underlying mechanisms LLPS, biophysical properties that drive MLO formation, their implications for We highlight recent advances understanding how physicochemical environment, molecular interactions, post-translational modifications regulate LLPS dynamics. offers an overview discovery current biomolecular condensate conditions diseases. article aims deliver latest insights by analyzing research, highlighting critical role organization. The discussion also covers membrane-associated condensates cell signaling, including those involving T-cell receptors, stress granules linked lysosomes, within Golgi apparatus. Additionally, potential targeting clinical settings is explored, promising avenues future research therapeutic interventions.

Language: Английский

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Phase separation-mediated biomolecular condensates and their relationship to tumor

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 21, 2024

Abstract Phase separation is a cellular phenomenon where macromolecules aggregate or segregate, giving rise to biomolecular condensates resembling "droplets" and forming distinct, membrane-free compartments. This process pervasive in biological cells, contributing various essential functions. However, when phase goes awry, leading abnormal molecular aggregation, it can become driving factor the development of diseases, including tumor. Recent investigations have unveiled intricate connection between dysregulated tumor pathogenesis, highlighting its potential as novel therapeutic target. article provides an overview recent research, with particular emphasis on role tumor, implications, outlines avenues for further exploration this intriguing field.

Language: Английский

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