Abstract LB-021: Impaired formation of homotypic cell-in-cell structures in human tumor cells lacking alpha-catenin expression

Abstract

Abstract Majority of internal lumens in our bodies are covered with a layer of epithelial cells, whose integrity is critical for the organs to function properly. The integrity of epithelial tissues depends on intact adherens junctions (AJs), which is a multiple-components complex comprising cadherins, the transmembrane adhesion receptors, and their cytoplasmic binding proteins such as p120-catenin and b-catenin etc. Functional AJs is coupled with actin filaments through linker molecules, of which a-catenin and EPLIN are best characterized. Actin polymerization and actomyosin contraction regulated by Rho GTPases and their effectors play important role in AJs maintenance and remodeling. Aberrations, structural or functional, in AJs were associated with a number of pathological conditions, such as infection, inflammation and tumors and the like. Recent studies indicated that AJs mediated the formation of cell-in-cell structures (CICs). CICs refer to the cellular structures formed between viable cells, in which one or more cells exist inside other ones. Early records on CICs could be dated back to last century, when pathologists identified this type of unusual structures in human tumor samples10. Recent progress showed that cell-in-cell structures are rather complex than initially described, and could be classified into homotypic or heterotypic CICs based on the cells involved. Heterotypic CICs are usually formed by penetration of lymphocytes into tumor cells through processes like emperitosis. Homotypic CICs are formed between cells from same type, for example, epithelial cells inside epithelial cells. Mechanisms like entosis and homotypic cell cannibalism (HoCC) are responsible for this type of CICs formation. Once formed, CICs usually result in death of the internalized cells, which lead to the conception that CICs formation is a process of cell death. Limited researches identified extensive involvement of CICs in several important biological processes including development, immune homeostasis and tumor development and evolution etc. Recently, we and others found that formation of homotypic CICs by entosis was dependent on intact AJs and polarized actomyosin contraction. Tumor cells lacking epithelial cadherins (E and P-cadherin) failed to form CICs, moreover, re-expression of E- or P-cadherin could efficiently induce CICs in these cells, suggesting that disrupting AJs is a mechanism whereby tumor cells escape entosis-mediated CICs formation. In this work, we found that tumor cells deficient of a-catenin, a key component of functional AJs, also displayed impaired CICs formation, which could be fixed by restored expression of a -catenin. Therefore, tumor cells could escape entotic CICs formation by targeting multiple AJs components including E-/P-cadherin and a-catenin, and CICs formation by entosis may constitute a novel mechanism underlying the tumor suppressive function imposed by a -catenin. Note: This abstract was not presented at the meeting. Citation Format: Manna Wang, Xiangkai Ning, Ang Chen, Hongyan Huang, Qiang Sun, Zhaolie Chen, Li Ma, Xiaoning Wang. Impaired formation of homotypic cell-in-cell structures in human tumor cells lacking alpha-catenin expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-021. doi:10.1158/1538-7445.AM2017-LB-021