E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms
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abstract
E-cadherin, an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike in carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on p-CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth.
Jolly, M. K., Ware, K. E., Xu, S., Gilja, S., Shetler, S., Yang, Y., ... Somarelli, J. A.
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Jolly, Mohit Kumar||Ware, Kathryn E||Xu, Shengnan||Gilja, Shivee||Shetler, Samantha||Yang, Yanjun||Wang, Xueyang||Austin, R Garland||Runyambo, Daniella||Hish, Alexander J||DeWitt, Suzanne Bartholf||George, Jason T||Kreulen, R Timothy||Boss, Mary-Keara||Lazarides, Alexander L||Kerr, David L||Gerber, Drew G||Sivaraj, Dharshan||Armstrong, Andrew J||Dewhirst, Mark W||Eward, William C||Levine, Herbert||Somarelli, Jason A
