RT Journal Article
SR Electronic
T1 E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP 1391
OP 1402
DO 10.1158/1541-7786.MCR-18-0763
VO 17
IS 6
A1 Jolly, Mohit Kumar
A1 Ware, Kathryn E.
A1 Xu, Shengnan
A1 Gilja, Shivee
A1 Shetler, Samantha
A1 Yang, Yanjun
A1 Wang, Xueyang
A1 Austin, R. Garland
A1 Runyambo, Daniella
A1 Hish, Alexander J.
A1 Bartholf DeWitt, Suzanne
A1 George, Jason T.
A1 Kreulen, R. Timothy
A1 Boss, Mary-Keara
A1 Lazarides, Alexander L.
A1 Kerr, David L.
A1 Gerber, Drew G.
A1 Sivaraj, Dharshan
A1 Armstrong, Andrew J.
A1 Dewhirst, Mark W.
A1 Eward, William C.
A1 Levine, Herbert
A1 Somarelli, Jason A.
YR 2019
UL http://mcr.aacrjournals.org/content/17/6/1391.abstract
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.