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E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms

Jolly, MK and Ware, KE and Xu, S and Gilja, S and Shetler, S and Yang, Y and Wang, X and Austin, RG and Runyambo, D and Hish, AJ and DeWitt, SB and George, JT and Kreulen, RT and Boss, M-K and Lazarides, AL and Kerr, DL and Gerber, DG and Sivaraj, D and Armstrong, AJ and Dewhirst, MW and Eward, WC and Levine, H and Somarelli, JA (2019) E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms. In: Molecular Cancer Research, 17 (6). pp. 1391-1402.

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Official URL: https://doi.org/10.1158/1541-7786.MCR-18-0763


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 mesenchymalto- 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. © 2019 American Association for Cancer Research.

Item Type: Journal Article
Publication: Molecular Cancer Research
Publisher: American Association for Cancer Research Inc.
Additional Information: The copyright for this article belongs to the Authors.
Keywords: cell adhesion molecule; small interfering RNA; transcription factor T bet; uvomorulin; cadherin; CDH1 protein, human; leukocyte antigen, adherens junction; anchorage independent growth; Article; cancer growth; cancer inhibition; cancer prognosis; cell adhesion; clinical outcome; controlled study; ectopic expression; epithelial mesenchymal transition; fibromyxosarcoma; gene knockdown; gene regulatory network; human; human cell; human tissue; intracellular signaling; leiomyosarcoma; liposarcoma; malignant peripheral nerve sheath tumor; mathematical model; metastasis free survival; osteosarcoma; overall survival; phenotypic plasticity; priority journal; protein expression; rhabdomyosarcoma; RNA interference; sarcoma; sarcoma cell; signal transduction; synovial sarcoma; cell proliferation; down regulation; epithelial mesenchymal transition; metabolism; physiology; prognosis; sarcoma; signal transduction; tumor cell line; upregulation, Antigens, CD; Cadherins; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Epithelial-Mesenchymal Transition; Humans; Prognosis; Sarcoma; Signal Transduction; Up-Regulation
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 25 Oct 2022 08:42
Last Modified: 25 Oct 2022 08:42
URI: https://eprints.iisc.ac.in/id/eprint/77526

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