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.