Abstract
Homotypic or entotic cell-in-cell invasion is an integrin-independent process observed in carcinoma cells exposed during conditions of low adhesion such as in exudates of malignant disease. Although active cell-in-cell invasion depends on RhoA and actin, the precise mechanism as well as the underlying actin structures and assembly factors driving the process are unknown. Furthermore, whether specific cell surface receptors trigger entotic invasion in a signal-dependent fashion has not been investigated. In this study, we identify the G-protein-coupled LPA receptor 2 (LPAR2) as a signal transducer specifically required for the actively invading cell during entosis. We find that G12/13 and PDZ-RhoGEF are required for entotic invasion, which is driven by blebbing and a uropod-like actin structure at the rear of the invading cell. Finally, we provide evidence for an involvement of the RhoA-regulated formin Dia1 for entosis downstream of LPAR2. Thus, we delineate a signaling process that regulates actin dynamics during cell-in-cell invasion.
Highlights
Entosis has been described as a specialized form of homotypic cell-in-cell invasion in which one cell actively crawls into another (Overholtzer et al, 2007)
This is further supported by the fact that homotypic cell-in-cell structures can be regularly found when tumor cells are released into fluid exudates such as ascites or during pleural carcinosis (Overholtzer and Brugge, 2008)
We investigated actin-mediated entotic invasion and delineate a signaling pathway downstream of the lysophosphatidic acid (LPA) receptor 2 (LPAR2) that targets the formin mDia1 for polarized actin assembly at the rear of the invading cell to drive cell-in-cell invasion
Summary
Entosis has been described as a specialized form of homotypic cell-in-cell invasion in which one cell actively crawls into another (Overholtzer et al, 2007) This occurs between tumor cells such as breast, cervical, or colon carcinoma cells and can be triggered by matrix detachment (Overholtzer et al, 2007), suggesting that loss of integrin-mediated adhesion may promote cell-in-cell invasion. This is further supported by the fact that homotypic cell-in-cell structures can be regularly found when tumor cells are released into fluid exudates such as ascites or during pleural carcinosis (Overholtzer and Brugge, 2008). We investigated actin-mediated entotic invasion and delineate a signaling pathway downstream of the LPAR2 that targets the formin mDia for polarized actin assembly at the rear of the invading cell to drive cell-in-cell invasion
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