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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Jolly, MK; Ware, KE; Xu, S; Gilja, S; Shetler, S; Yang, Y; Wang, X; Austin, RG; Runyambo, D; Hish, AJ; Bartholf DeWitt, S; George, JT; Kreulen, RT; Boss, M-K; Lazarides, AL; Kerr, DL; Gerber, DG; Sivaraj, D; Armstrong, AJ; Dewhirst, MW; Eward, WC; Levine, H; Somarelli, JA

Published Date

  • June 2019

Published In

Volume / Issue

  • 17 / 6

Start / End Page

  • 1391 - 1402

PubMed ID

  • 30862685

Pubmed Central ID

  • 30862685

Electronic International Standard Serial Number (EISSN)

  • 1557-3125

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.MCR-18-0763

Language

  • eng

Conference Location

  • United States