E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms
Mohit Kumar Jolly,
Kathryn E Ware,
Alexander J Hish,
Suzanne Bartholf DeWitt,
Jason T George,
R. Timothy Kreulen,
Alexander L Lazarides,
David L Kerr,
Drew G Gerber,
Andrew J Armstrong,
Mark W Dewhirst,
William C Eward,
Jason A Somarelli
Posted 15 Jun 2018
bioRxiv DOI: 10.1101/347815 (published DOI: 10.1158/1541-7786.MCR-18-0763)
Posted 15 Jun 2018
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.
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