The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis.

Nathalie Duffey,Qiang Lan,Girieca Lorusso,Yu-Ting Huang,Curzio Rüegg

doi:10.18632/oncotarget.13677

Abstract

Matricellular proteins play multiple roles in primary tumor growth, local invasion and tumor angiogenesis. However, their contribution to metastasis and the putative mechanisms involved are less well characterized. In ER-negative human breast cancer, elevated expression levels of the matricellular protein Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive progression. Here, we investigated the role of CYR61 in breast cancer lung metastasis using the triple negative human breast cancer cell lines MDA-MB-231 and SUM159. Silencing of CYR61 significantly decreased lung metastasis from tumors orthotopically implanted in pre-irradiated or naive mammary tissue and upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell extravasation to the lung during the first 24 hours after tail vein injection. In contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection had no impact on lung metastasis formation. In vitro experiments revealed that CYR61 silencing decreased cancer cell transendothelial migration and motility, reduced CYR61 levels present at the cell surface and sensitized cancer cells to anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under non-adhesive conditions relied, at least partially, on β1 integrin ligation and AMPKα signaling while it was independent of AKT, FAK and ERK1/2 activation. Our data provide the first evidence that CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and protecting from anoikis during initial seeding to the lung. The uncovered CYR61-β1 integrin-AMPKα axis may serve as a potential therapeutic target to prevent breast cancer metastasis to the lung.

Highlights

In over 90% of the cases, cancer-related mortality is due to the formation of distant metastasis
By combining in vivo and in vitro experiments we demonstrate here that Cysteine-rich angiogenic inducer 61 (CYR61) promotes lung metastasis of triple-negative breast cancer by facilitating two events relevant to the late steps of metastatic dissemination: firstly, by enhancing extravasation of cancer cells into the lung and, secondly, by conferring resistance to anoikis, at least in part, through the activation of AMPKα pathway but not through AKT, FAK or ERK1/2 signaling
Most of the published in vivo data about CYR61 focus on its function during primary tumor development, especially primary tumor growth, tumor angiogenesis and local invasion

Summary

Introduction

In over 90% of the cases, cancer-related mortality is due to the formation of distant metastasis. The tumor microenvironment, including extracellular matrix (ECM) proteins, has emerged as a crucial promoter of local tumor progression, invasion and metastasis [4, 5]. Matricellular proteins secreted by cancer cells and stromal cells are non-structural ECM components of the microenvironment. After release into the extracellular space, matricellular proteins bind to cell surface receptors and extracellular matrix proteins to regulate multiple cellular functions, including proliferation, invasion, and metastatic dissemination [6]. Several families of matricellular proteins have been identified, including fibulins, osteopontin, periostin, SPARCs, tenascins, and thrombospondins, and www.impactjournals.com/oncotarget their diversified functions in cancer progression are being gradually unveiled [7]

Methods

Results

Conclusion