June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Role of exosomes in liver metastasis of uveal melanoma
Author Affiliations & Notes
  • Angels Fabra
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Raquel Ramos
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Eduard Cabré
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Antonia Vinyals
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Jose Maria Caminal
    Ophthalmology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalunya, Spain
  • J Vaquero
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Daniel Lorenzo
    Ophthalmology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalunya, Spain
  • Josep M. Piulats
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Montse Gomá
    Ophthalmology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalunya, Spain
  • Cristina Gutierrez
    Ophthalmology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalunya, Spain
  • Ester Gonzalez Sanchez
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • I. Fabregat
    ONCOBELL, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Footnotes
    Commercial Relationships   Angels Fabra None; Raquel Ramos None; Eduard Cabré None; Antonia Vinyals None; Jose Maria Caminal None; J Vaquero None; Daniel Lorenzo None; Josep M. Piulats None; Montse Gomá None; Cristina Gutierrez None; Ester Gonzalez Sanchez None; I. Fabregat None
  • Footnotes
    Support  ISCIII PI 18/ 001131 SPAIN and AECC GCB15152978SOEN
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2617. doi:
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    • Get Citation

      Angels Fabra, Raquel Ramos, Eduard Cabré, Antonia Vinyals, Jose Maria Caminal, J Vaquero, Daniel Lorenzo, Josep M. Piulats, Montse Gomá, Cristina Gutierrez, Ester Gonzalez Sanchez, I. Fabregat; Role of exosomes in liver metastasis of uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2617.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Exosomes are small membrane vesicles that carry functional biomolecules derived from donor cells and can be horizontally transferred to recipient cells.
We aim to analyze whether uveal melanoma -derived exosomes were able to condition liver cells to create a favorable niche for the metastatic colonization and outgrowth of uveal melanoma cells

Methods : We isolated exosomes by differential ultracentrifugation from primary and metastatic UM cell lines with a common genetic background. Secretome was obtained from cells growing in vitro either in 2D or 3D conditions. Exosomes were characterized by electron microscopy; proteomic analysis was performed by LC-MSMS (LTQ-Orbitrap), and exosomal biomarkers by immunoblot. The uptake of exosomes by human liver cells was assessed by immunofluorescence. Human liver stellate cells (LX2) and macrophages (THP1) in co-culture in vitro, were exposed to uveal melanoma-derived exosomes. Transcriptomic and proteomic analyses were studied after the exosomal treatments.

Results : We identified 3241 proteins in exosomes from the isogenic UM cell lines, 895 of which were differentially expressed between invasive and non-invasive UM cells and the identified targets were validated by immunoblot. Interestingly, bioinformatic analysis showed that invasive UM cells display an enrichment in proteins involved in cell migration, invasion and signaling pathways such as WNT, IGF-1R, TGFß and NFkB, as well as specific integrins and focal adhesion proteins.
Moreover, we assessed the uptake of UM-derived exosomes by macrophages (THP1 cells) which contribute to the activation and reprogramming of human hepatic stellate cells (HSCs). HSCs adopt then a proangiogenic phenotype by upregulation of VEGF, IL8 and IL1ß; a pro-inflammatory and pro-fibrotic environment via upregulation of extracellular matrix molecules such as FN1 and FN-EDA and CCN2 and a promigratory phenotype. These changes are at least in part, orchestrated by the induction of ZEB1 and PRRX1 transcription factors.

Conclusions : Our results indicate that uveal melanoma-derived exosomes have a key role in the education of the Human Liver Stellate Cells favoring the development of the pre-metastatic niche in the liver that tilt in favor of metastasis. Furthermore, uveal exosomes can be used as biomarkers of metastatic disease and their cargo reflect the plasticity of uveal melanoma cells and announces possible new therapeutic targets for uveal melanoma.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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