Functional validation of driver mutation-specific uveal melanoma biomarkers: role of COL9A3 in cancer cell plasticity.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος:	Functional validation of driver mutation-specific uveal melanoma biomarkers: role of COL9A3 in cancer cell plasticity.
Συγγραφείς:	van den Bosch Q; Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands.; Department of Clinical Genetics, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands., Verdijk RM; Department of Pathology, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands., Fadlelseed H; National Ophthalmic Pathology Laboratory, Royal Victoria Eye and Ear Hospital and Research Foundation, Dublin, Ireland., van den Bosch T; Department of Pathology, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands., Owens S; National Ophthalmic Pathology Laboratory, Royal Victoria Eye and Ear Hospital and Research Foundation, Dublin, Ireland., Kennedy S; National Ophthalmic Pathology Laboratory, Royal Victoria Eye and Ear Hospital and Research Foundation, Dublin, Ireland., Kilic E; Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands., Brosens E; Department of Clinical Genetics, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands.
Πηγή:	The Journal of pathology [J Pathol] 2026 Oct; Vol. 270 (2), pp. 226-240. Date of Electronic Publication: 2026 Jul 21.
Τύπος έκδοσης:	Journal Article
Γλώσσα:	English
Στοιχεία περιοδικού:	Publisher: John Wiley And Sons Country of Publication: England NLM ID: 0204634 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-9896 (Electronic) Linking ISSN: 00223417 NLM ISO Abbreviation: J Pathol Subsets: MEDLINE
Imprint Name(s):	Publication: Chichester : John Wiley And Sons Original Publication: London, Oliver & Boyd.
Ιατρικοί όροι (MeSH):	Uveal Neoplasms/genetics , Uveal Neoplasms/pathology , Uveal Neoplasms/metabolism , Melanoma/genetics , Melanoma/pathology , Melanoma/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Mutation* , Cell Plasticity*, Tumor Suppressor Proteins/genetics ; Ubiquitin Thiolesterase/genetics ; RNA Splicing Factors/genetics ; RNA Splicing Factors/metabolism ; Eukaryotic Initiation Factor-1/genetics ; Eukaryotic Initiation Factor-1/metabolism ; Humans ; Uveal Melanoma ; Animals ; Zebrafish ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Female
Περίληψη:	Uveal melanoma (UM) is a deadly ocular malignancy with well-described genetic alterations that predict disease outcome. However, our current understanding of the biological underpinnings of high-risk uveal melanoma progression remains relatively limited. Using RNA expression profiles from 250 patients with UM, we identified 12 novel biomarkers associated with high-risk UM, with protein expression level validation of the top two candidates: the transcriptional regulator RBFOX2 and matrix protein COL9A3. Moreover, we investigated the functional contribution of COL9A3 via its overexpression in EIF1AX^mut and BAP1^mut UM cell lines. Our data suggest that COL9A3 enhances cell motility and cell proliferation and alters morphology specifically in BAP1^mut UM cells. Furthermore, zebrafish xenograft studies revealed increased cell dissemination in a EIF1AX^mut UM cell line upon overexpression of COL9A3, whereas a BAP1^mut UM cell line remained unchanged under wild-type conditions. Interestingly, RNA sequencing revealed a high-stress profile by upregulated metabolic activity and loss of protein translation due to COL9A3 overexpression. BAP1^mut UM appears to adapt to this stress by upregulation of plasticity markers, such as CD44, Nestin, EZH2, ABCB5, PAX3 and CD166, as a coping mechanism. These markers are known as differentiation markers during the development of melanocyte biogenesis and are implicated in plasticity in other high-risk cancers. The relationship between COL9A3 and plasticity was validated by multiplex immunohistochemistry of formalin-fixed paraffin-embedded (FFPE) tissue, which demonstrated colocalization of COL9A3, CD44 and Nestin. BAP1^mut-UM samples presented higher levels of COL9A3, CD44 and Nestin expression than EIF1AX^mut or SF3B1^mut UM samples based on the mean fluorescent intensity of each marker. A positive correlation between COL9A3 and Nestin expression in triple-positive cells, irrespective of the UM subtype, was observed. Collectively, our findings suggest that COL9A3 is a novel high-risk biomarker that may contribute to UM cell plasticity and is most prevalent in BAP1^mut UM. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. (© 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
References:	Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7293-8. (PMID: 20368466) Invest Ophthalmol Vis Sci. 2024 Aug 1;65(10):26. (PMID: 39163035) Onco Targets Ther. 2020 Nov 27;13:12243-12252. (PMID: 33273829) Nat Rev Cancer. 2013 Mar;13(3):153-9. (PMID: 23550303) Cancer. 1997 Apr 1;79(7):1299-303. (PMID: 9083150) N Engl J Med. 2023 Dec 14;389(24):2256-2266. (PMID: 37870955) Front Pharmacol. 2023 Jan 06;13:1098800. (PMID: 36686663) Cancer Res. 2011 Feb 1;71(3):666-74. (PMID: 21135111) Nat Rev Dis Primers. 2020 Apr 9;6(1):24. (PMID: 32273508) Cancer Inform. 2007 Feb 04;3:11-7. (PMID: 19455231) Cancer Cell Int. 2019 Jun 28;19:172. (PMID: 31297036) Cancers (Basel). 2022 Jul 28;14(15):. (PMID: 35954332) Br J Cancer. 2012 Jan 17;106(2):243-7. (PMID: 22187039) Int J Exp Pathol. 2013 Apr;94(2):75-92. (PMID: 23419153) J Exp Clin Cancer Res. 2019 Jun 24;38(1):277. (PMID: 31234902) Int J Genomics. 2023 Sep 7;2023:9942663. (PMID: 37719786) Cancer Cell. 2017 Aug 14;32(2):204-220.e15. (PMID: 28810145) RNA Biol. 2017 Sep 2;14(9):1138-1152. (PMID: 27911188) Can J Ophthalmol. 2004 Jun;39(4):409-21. (PMID: 15327107) Genome Res. 2021 Oct;31(10):1719-1727. (PMID: 34599005) Eur J Hum Genet. 2021 May;29(5):881-886. (PMID: 33633367) Br J Cancer. 2017 Sep 5;117(6):884-887. (PMID: 28809862) Curr Biol. 2007 Nov 20;17(22):1972-7. (PMID: 17980597) Cancers (Basel). 2019 Jun 12;11(6):. (PMID: 31212861) Nature. 2009 Jan 29;457(7229):599-602. (PMID: 19078957) Int J Mol Sci. 2025 Oct 07;26(19):. (PMID: 41097013) Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15149-54. (PMID: 11742071) Cell Death Dis. 2021 Dec 20;13(1):10. (PMID: 34930901) Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772) J Biol Chem. 2004 Dec 3;279(49):51677-87. (PMID: 15383545) Front Oncol. 2020 Dec 18;10:575569. (PMID: 33425730) Mol Oncol. 2014 Dec;8(8):1508-20. (PMID: 24994677) Cell Rep. 2023 Sep 26;42(9):113132. (PMID: 37708024) Cancer Res. 1989 Apr 1;49(7):1885-9. (PMID: 2924328) BMC Med Genomics. 2021 Mar 10;14(1):75. (PMID: 33691689) Cell. 2017 Oct 19;171(3):540-556.e25. (PMID: 28988769) Sci Rep. 2022 Jan 7;12(1):42. (PMID: 34997020) J Comput Biol. 2002;9(3):505-11. (PMID: 12162889) Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4254-62. (PMID: 18552379) Biomaterials. 2017 Jun;128:147-159. (PMID: 28327460) Ophthalmology. 2012 Aug;119(8):1596-603. (PMID: 22521086) Nucleic Acids Res. 2009 Jan;37(Database issue):D885-90. (PMID: 18940857) Invest Ophthalmol Vis Sci. 2003 Nov;44(11):4651-9. (PMID: 14578381) Signal Transduct Target Ther. 2021 Apr 23;6(1):153. (PMID: 33888679) Int J Cancer. 1995 Jul 17;62(2):155-61. (PMID: 7622289) Heliyon. 2024 Aug 13;10(16):e36164. (PMID: 39247375) Science. 2010 Dec 3;330(6009):1410-3. (PMID: 21051595) Cancer Discov. 2022 Jan;12(1):31-46. (PMID: 35022204) Ophthalmology. 2016 May;123(5):1118-28. (PMID: 26923342) Br J Cancer. 2013 Jul 23;109(2):444-51. (PMID: 23799842) Biochim Biophys Acta Rev Cancer. 2024 Jan;1879(1):189055. (PMID: 38104908) J Nat Med. 2021 Jun;75(3):590-601. (PMID: 33713277) Nat Genet. 2013 Aug;45(8):933-6. (PMID: 23793026) Am J Med Genet A. 2014 Jan;164A(1):42-7. (PMID: 24273071)
Grant Information:	2019-7 Landelijke Stichting voor Blinden en Slechtzienden; 6.2.0 Combined Ophthalmic Research Rotterdam (CORR); HV/AB/B20200043 Rotterdamse Stichting Blindenbelangen; 2019-07 Algemene Nederlandse Vereniging ter voorkoming van Blindheid
Contributed Indexing:	Keywords: BAP1 mutation; COL9A3; biomarkers; cell plasticity; tumor microenvironment; uveal melanoma; zebrafish xenograft
Substance Nomenclature:	0 (Biomarkers, Tumor) 0 (BAP1 protein, human) 0 (Tumor Suppressor Proteins) EC 3.4.19.12 (Ubiquitin Thiolesterase) 0 (eukaryotic peptide initiation factor-1A) 0 (RNA Splicing Factors) 0 (Eukaryotic Initiation Factor-1)
Entry Date(s):	Date Created: 20260722 Date Completed: 20260915 Latest Revision: 20260917
Update Code:	20260917
PubMed Central ID:	PMC13576891
DOI:	10.1002/path.70094
PMID:	42482451
Βάση Δεδομένων:	MEDLINE

Full Text Finder

Περιγραφή
ISSN:	1096-9896
DOI:	10.1002/path.70094