PT - JOURNAL ARTICLE AU - Jolly, Mohit Kumar AU - Ware, Kathryn E. AU - Xu, Shengnan AU - Gilja, Shivee AU - Shetler, Samantha AU - Yang, Yanjun AU - Wang, Xueyang AU - Austin, R. Garland AU - Runyambo, Daniella AU - Hish, Alexander J. AU - Bartholf DeWitt, Suzanne AU - George, Jason T. AU - Kreulen, R. Timothy AU - Boss, Mary-Keara AU - Lazarides, Alexander L. AU - Kerr, David L. AU - Gerber, Drew G. AU - Sivaraj, Dharshan AU - Armstrong, Andrew J. AU - Dewhirst, Mark W. AU - Eward, William C. AU - Levine, Herbert AU - Somarelli, Jason A. TI - E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms AID - 10.1158/1541-7786.MCR-18-0763 DP - 2019 Jun 01 TA - Molecular Cancer Research PG - 1391--1402 VI - 17 IP - 6 4099 - http://mcr.aacrjournals.org/content/17/6/1391.short 4100 - http://mcr.aacrjournals.org/content/17/6/1391.full SO - Mol Cancer Res2019 Jun 01; 17 AB - CDH1 (also known as 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-to-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 carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-to-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 CREB1 (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on 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.Implications: We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.