E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms.

Abstract

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.

• Authors: Mohit Kumar Jolly, Kathryn E Ware, Shengnan Xu, Shivee Gilja, Samantha Shetler, Yanjun Yang, Xueyang Wang, R Garland Austin, Daniella Runyambo, Alexander J Hish, Suzanne Bartholf DeWitt, Jason T George, R Timothy Kreulen, Mary-Keara Boss, Alexander L Lazarides, David L Kerr, Drew G Gerber, Dharshan Sivaraj, Andrew J Armstrong, Mark W Dewhirst, William C Eward, Herbert Levine, Jason A Somarelli
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 17 Issue 6 Pg. 1391-1402 (06 2019) ISSN: 1557-3125 [Electronic] United States
• PMID: 30862685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins

Topics

• Antigens, CD (metabolism)
• Cadherins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Down-Regulation (physiology)
• Epithelial-Mesenchymal Transition (physiology)
• Humans
• Prognosis
• Sarcoma (metabolism)
• Signal Transduction (physiology)
• Up-Regulation (physiology)