E-cadherin represses anoikis resistance in sarcomas through both signaling and mechanical mechanisms

Jolly, M. K.; Ware, K. E.; Xu, S.; Gilja, S.; Shetler, S.; Yang, Y.; Wang, X.; Austin, G.; Hish, A. J.; Bartholf DeWitt, S.; George, J. T.; Kreulen, R. T.; Boss, M.-K.; Lazarides, A. L.; Kerr, D. L.; Gerber, D. G.; Armstrong, A. J.; Dewhirst, M. W.; Eward, W. C.; Levine, H.; Somarelli, J. A.

doi:10.1101/347815

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bioRxiv · 10.1101/347815

E-cadherin represses anoikis resistance in sarcomas through both signaling and mechanical mechanisms

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Abstract

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-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 in carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-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 CREB (p-CREB) and the transcription factor, TBX2, to inhibit anoikis resistance. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on p-CREB levels and restores anoikis sensitivity to 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 inducing anoikis and restricting colony growth.

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Jolly, M. K., Ware, K. E., Xu, S., Gilja, S., Shetler, S., Yang, Y., Wang, X., Austin, G., Hish, A. J., Bartholf DeWitt, S., George, J. T., Kreulen, R. T., Boss, M.-K., Lazarides, A. L., Kerr, D. L., Gerber, D. G., Armstrong, A. J., Dewhirst, M. W., Eward, W. C., Levine, H., Somarelli, J. A.. 2018-06-15. E-cadherin represses anoikis resistance in sarcomas through both signaling and mechanical mechanisms. https://doi.org/10.1101/347815

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