Modeling ANXA2-overexpressing circulating tumor cells homing and high throughput screening for metastasis impairment in endometrial carcinomas

Abstract

Cèl·lules tumorals circulants; Micrometàstasi; Daunorrubicina

Células tumorales circulantes; Micrometástasis; Daunorrubicina

Circulating tumor cells; Micrometastasis; Daunorubicin

Endometrial cancer (EC) is the most common neoplasm of the female reproductive tract in the developed world. Patients usually are diagnosed in early stage having a good prognosis. However, up to 20–25% of patients are diagnosed in advanced stages and have a higher risk of recurrence, making the prognosis worse. Previously studies identified ANXA2 as a predictor of recurrent disease in EC even in low risk patients. Furthermore, Circulating Tumor Cells (CTC) released from the primary tumor into the bloodstream, are plasticity entities responsible of the process of metastasis, becoming into an attractive clinical target. In this work we validated ANXA2 expression in CTC from high-risk EC patients. After that, we modelled in vitro and in vivo the tumor cell attachment of ANXA2-expressing CTC to the endothelium and the homing for the generation of micrometastasis. ANXA2 overexpression does not provide an advantage in the adhesion process of CTC, but it could be playing an important role in more advanced steps, conferring a greater homing capacity. We also performed a high-throughput screening (HTS) for compounds specifically targeting ANXA2, and selected Daunorubicin as candidate hit. Finally, we validated Daunorubicin in a 3D transendothelial migration system and also in a in vivo model of advanced EC, demonstrating the ability of Daunorubicin to inhibit the proliferation of ANXA2-overexpressing tumor cells.

This work was supported by grants from the Instituto de Salud Carlos III ( ISCIII ), grant PI17/01919 and PI20/00969 , co-financed by the European Regional Development Fund (FEDER); from Fundación Científica de la Asociación Española Contra el Cáncer (AECC), Grupos Clínicos Coordinados 2018; Xunta de Galicia ( ED431C 2018/21 ); Ministry of Economy and Competiveness (Innopharma Project) and from CIBERONC ( CB16/12/00328 ); Carolina Herrero is supported by a predoctoral i-PFIS fellowship from Instituto de Salud Carlos III ( IFI17/00047 ).