June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Uncovering the Mechanisms Behind Hepatic Microenvironment Remodeling in Metastatic Uveal Melanoma
Author Affiliations & Notes
  • Ioana Fugaru
    Université Laval, Quebec, Quebec, Canada
    Centre de Recherche du CHU de Québec-Université Laval, Quebec, Quebec, Canada
  • Julie Bérubé
    Centre de Recherche du CHU de Québec-Université Laval, Quebec, Quebec, Canada
  • Narjes Babchia
    INSERM UMR991, Université de Rennes 1, Rennes, France
  • Cédric Coulouarn
    INSERM UMR991, Université de Rennes 1, Rennes, France
  • Frédéric Mouriaux
    INSERM UMR991, Université de Rennes 1, Rennes, France
  • Solange Landreville
    Université Laval, Quebec, Quebec, Canada
    Centre de Recherche du CHU de Québec-Université Laval, Quebec, Quebec, Canada
  • Footnotes
    Commercial Relationships   Ioana Fugaru, None; Julie Bérubé, None; Narjes Babchia, None; Cédric Coulouarn, None; Frédéric Mouriaux, None; Solange Landreville, None
  • Footnotes
    Support  Fonds de recherche du Québec – Santé (FRQS), Vision Health Research Network, Canada Foundation for Innovation
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3968. doi:
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      Ioana Fugaru, Julie Bérubé, Narjes Babchia, Cédric Coulouarn, Frédéric Mouriaux, Solange Landreville; Uncovering the Mechanisms Behind Hepatic Microenvironment Remodeling in Metastatic Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3968.

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

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Abstract

Purpose : 50% of uveal melanoma (UM) patients develop liver metastases by 10 years after the diagnosis of the primary tumor. Powerful prognostic tools help determine the likelihood of metastatic progression, however, no cure is currently available for patients with metastatic disease. Activated hepatic stellate cells (HSCs) are involved in hepatic fibrosis during the metastatic progression of colorectal and pancreatic cancers; yet their role in the metastatic progression of UM remains elusive. We postulate that HSCs enable metastatic UM cells (UMCs) to exit dormancy and enter a proliferative state by secreting cytokines and growth factors and by remodeling the hepatic extracellular matrix (ECM). Our research project aims to develop both 2D and 3D models to investigate ECM remodeling processes and bilateral interactions between HSCs and UMCs.

Methods : Matrix sheets were synthetized by HSCs using the self-assembly approach of tissue engineering. UMCs were embedded into the 3D hepatic stromas and matrix proteins were analyzed by confocal microscopy. In addition, migration tests, cytokine proteome profiling, and gene profiling were performed in order to study the bilateral interactions between HSCs and primary or metastatic UMCs.

Results : We demonstrated that UMCs altered the ECM architecture of reconstructed HSC stromas. We observed a significant increase of transcripts/proteins associated to matrix remodeling such as fibronectin, lysyl oxidase like 4, chitinase 3 like 1 and plasminogen activator urokinase receptor in samples derived from HSCs co-cultured with metastatic UMCs. In HSCs/UMCs co-cultures, cell migration was faster and the secretome showed an increase of pro-tumoral cytokines, such as VEGF and GDF-15.

Conclusions : Co-culturing HSCs with metastatic UMCs resulted in ECM remodeling and increased secretion of pro-inflammatory, pro-angiogenic and pro-invasive cytokines. Our project aims to identify molecules involved in the development of a permissive metastatic microenvironment in the liver. By targeting components of the stromal response of HSCs, we might maintain liver micrometastases in permanent dormancy and have a major impact on patient survival.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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