CDH6-activated αIIbβ3 crosstalks with α2β1 to trigger cellular adhesion and invasion in metastatic ovarian and renal cancers.

Rubén A Bartolomé,Javier Robles,Miranda Burdiel,José Ignacio Casal,Ángela Martin‐Regalado,Juan I Imbaud,Laura Pintado‐Berninches,Marta Jaén,Carmen Aizpurúa

doi:10.1002/1878-0261.12947

Rubén A Bartolomé, Javier Robles + Show 7 more

Open Access

https://doi.org/10.1002/1878-0261.12947

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Abstract

Cadherin 6 (CDH6) is significantly overexpressed in advanced ovarian and renal cancers. However, the role of CDH6 in cancer metastasis is largely unclear. Here, we investigated the impact of CDH6 expression on integrin‐mediated metastatic progression. CDH6 preferentially bound to αIIbβ3 integrin, a platelet receptor scarcely expressed in cancer cells, and this interaction was mediated through the cadherin Arginine–glycine–aspartic acid (RGD) motif. Furthermore, CDH6 and CDH17 were found to interact with α2β1 in αIIbβ3low cells. Transient silencing of CDH6, ITGA2B, or ITGB3 genes caused a significant loss of proliferation, adhesion, invasion, and lung colonization through the downregulation of SRC, FAK, AKT, and ERK signaling. In ovarian and renal cancer cells, integrin αIIbβ3 activation appears to be a prerequisite for proper α2β1 activation. Interaction of αIIbβ3 with CDH6, and subsequent αIIbβ3 activation, promoted activation of α2β1 and cell adhesion in ovarian and renal cancer cells. Additionally, monoclonal antibodies specific to the cadherin RGD motif and clinically approved αIIbβ3 inhibitors could block pro‐metastatic activity in ovarian and renal tumors. In summary, the interaction between CDH6 and αIIbβ3 regulates α2β1‐mediated adhesion and invasion of ovarian and renal cancer metastatic cells and constitutes a therapeutic target of broad potential for treating metastatic progression.

Highlights

Ovarian cancer is considered the fifth cause of cancer death in women [1] and roughly comprises the histological subtypes of serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%), with distinct molecular alterations [2]
Cadherin 6 (CDH6) was highly expressed in ovarian (OVCAR3 and SKOV-3) and renal (RCC4 and 786-O) cancer cell lines except in CAKI-1 and A-2780, while Cadherin 17 (CDH17) was expressed in all cell lines, with RCC4, 786-O, and OVCAR3 exhibiting the highest amounts (Fig. 1A)
All cell lines were positive for a2, aIIb, b1, and b3 integrin subunits, except for CAKI-1 cells being negative for a2 and aIIb (Fig. 1A). av-integrin subunit was Molecular Oncology (2021) a 2021 The Authors

Summary

Introduction

Ovarian cancer is considered the fifth cause of cancer death in women [1] and roughly comprises the histological subtypes of serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%), with distinct molecular alterations [2]. Ovarian cancer causes a rapid and early metastasis to peritoneum and omentum, associated with ascites formation [4]. Further dissemination sites for metastatic ovarian cancer include liver and lung metastasis [5,6]. The Arginine–glycine–aspartic acid (RGD)-containing cadherin 6 (CDH6, K-cadherin) is often highly expressed and has been determined in 70% of high-grade serous, 45% of low-grade serous, 27% of clear cell, 25% of endometrioid, and 3.6% of mucinous cases, with a preferential expression in stage III cancers, except for high-grade serous, which show. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

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