Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles.

Maren Voglstaetter,Carina Blaue,Thalia Erbes,Paul Jank,Arend Koch,Marina Veil,Jonathan Sleeman,Ghamartaj Hossein,Christine Sers,Jochen Dindorf,Irina Nazarenko,Tanja Gainey‐Schleicher,Bernhard Homey,Wilko Thiele,Claude Boucheix,Gerhard Puetz,Andreas Hippe,Jerome Nouvel,Jubin Kashef,Marie Follo,Richa Khanduri,Andreas S Baur ,Clemens M Franz ,Andreas Thomsen ,Andrea M Gross ,Florian Roßner ,Christiane Waller ,Elena Grueso-Navarro ,Céline Greco

doi:10.1002/path.5281

Abstract

Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8+ tumours formed multiple liver and spleen metastases, while Tspan8− tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up‐regulation of E‐cadherin and down‐regulation of Twist, p120‐catenin, and β‐catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal–epithelial transition. Furthermore, Tspan8+ cells exhibited enhanced cell–cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several‐fold increase in EV number in cell culture and the circulation of tumour‐bearing animals. We observed increased protein levels of E‐cadherin and p120‐catenin in these EVs; furthermore, Tspan8 and p120‐catenin were co‐immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Highlights

The need to enhance understanding of how metastases develop and progress has initiated many studies
Tspan8 is expressed in breast cancer primary lesions and in metastases in different organs While the majority of tetraspanins are ubiquitously expressed, in a healthy organism, the presence of TSPAN8 is mainly restricted to the digestive tract (Figure 1A) [20]
To address the possibility of TSPAN8 playing a role in breast cancer, we first tested seven breast cancer cell lines [22] for TSPAN8 expression and observed that only MDA-MB-361 cells derived from brain metastases exhibited high levels of TSPAN8

Summary

Introduction

The need to enhance understanding of how metastases develop and progress has initiated many studies. The role of epithelial–mesenchymal transition (EMT) has come to the fore, suggesting that a proportion of primary tumour cells acquire mesenchymal properties to pass the basal membrane, disseminate into the blood stream or lymphatic system, and colonise distant organs [1]. Based on this clinical observation, it has been proposed that a reverse process, so-called mesenchymal–epithelial transition (MET), which triggers cancer cell redifferentiation, takes place in a portion of metastases and supports their growth [2]. We propose a new function of Tspan as an EMT–MET regulator in breast cancer

Methods

Results

Conclusion