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

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.

published proceedings

  • Mol Cancer Res

altmetric score

  • 1

author list (cited authors)

  • Jolly, M. K., Ware, K. E., Xu, S., Gilja, S., Shetler, S., Yang, Y., ... Somarelli, J. A.

citation count

  • 28

complete list of authors

  • Jolly, Mohit Kumar||Ware, Kathryn E||Xu, Shengnan||Gilja, Shivee||Shetler, Samantha||Yang, Yanjun||Wang, Xueyang||Austin, R Garland||Runyambo, Daniella||Hish, Alexander J||Bartholf DeWitt, Suzanne||George, Jason T||Kreulen, R Timothy||Boss, Mary-Keara||Lazarides, Alexander L||Kerr, David L||Gerber, Drew G||Sivaraj, Dharshan||Armstrong, Andrew J||Dewhirst, Mark W||Eward, William C||Levine, Herbert||Somarelli, Jason A

publication date

  • June 2019