American Association for Cancer Research
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Figure S4 from E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms

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posted on 2023-04-03, 17:28 authored by 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

S4. E-cadherin induces E- to N-cadherin switching in sarcoma cells.

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Center for Theoretical Biological Physics

Directorate for Mathematical & Physical Sciences

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ARTICLE 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. We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.