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PO-12 - The key role of talin-1 in cancer cell extravasation dissected through human vascularized 3D microfluidic model.

Abstract：

INTRODUCTION:Metastases are responsible for more than 90% of cancer related mortality. The hematogenous metastatic invasion is a complex process in which the endothelium plays a key role. Extravasation is a dynamic process involving remodeling and change in cell shape and in cytoskeleton whereby a series of strongly dependent interactions between CTCs and endothelium occurs [1]. Talins are proteins regulating focal adhesions and cytoskeleton remodeling. Talin-1 seems to be involved in the aggressiveness, motility, survival and invadopodia formation of cancer cells throughout the entire metastatic cascade [2], being up-regulated in breast cancer cells and mutated in sarcomas. Understand the implication of talin-1 in extravasation could facilitate the design of new therapies and finally fight cancer. AIM:We hypothesized that Talin-1 could be specifically involved in extravasation driving each of its steps. MATERIALS AND METHODS:We developed a human 3D microfluidic model that enables the study of human cancer cell extravasation within a perfusable human microvascularized organ specific environment[3]. For the study of extravasation we applied microfluidic approach through the development of a microfluidic device in which endothelial cells and fibroblasts generated a 3D human functional vascular networks. Microvessel characterization was performed with immunofluorescence and permeability assays. We knocked-down talin-1 in triple negative breast cancer cell line MDA-MB231 and metastatic fibro-sarcoma cell line HT1080 with SiRNA and verified by Western-blot. Cancer cells were then perfused in the vessels and extravasation monitored through confocal imaging. RESULTS:We developed a human vascularized 3D microfluidic device with human perfusable capillary-like structures embedded in fibrin matrix, characterized by mature endothelium markers and physiological permeability (1.5±0.76)×10(-6) cm/s. We focused on the role of Talin-1 in adhesion to endothelium, trans-endothelial migration (TEM) and early invasion. Adhesion to the endothelium, TEM and migration within the ECM were monitored through confocal analyses. We demonstrated that Talin-1 KD significantly reduced the adhesion efficiency and TEM in both cell lines. Early invasion was also strongly and statistically reduced by the SiRNA treatment in both cell lines. CONCLUSIONS:We proved Talin-1 function in driving the extravasation mechanism in a human 3D vascularized environment. We demonstrated that Talin-1 is involved in each part of extravasation significantly affecting adhesion, TEM and the invasion stages. Targeting this protein could thus be an effective strategy to block metastasis.

journal_name

Thromb Res

journal_title

Thrombosis research

authors

Gilardi M,Bersini S,Calleja AB,Kamm RD,Vanoni M,Moretti M

doi

10.1016/S0049-3848(16)30145-1

subject

Has Abstract

pub_date

2016-04-01 00:00:00

pages

S180-1

eissn

0049-3848

issn

1879-2472

pii

S0049-3848(16)30145-1

journal_volume

140 Suppl 1

pub_type

杂志文章

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PO-12 - The key role of talin-1 in cancer cell extravasation dissected through human vascularized 3D microfluidic model.