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

Autor:	Jolly MK; Center for Theoretical Biological Physics, Rice University, Houston, Texas., Ware KE; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Xu S; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Gilja S; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Shetler S; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Yang Y; Center for Theoretical Biological Physics, Rice University, Houston, Texas.; Department of Applied Physics, Rice University, Houston, Texas., Wang X; School of Medicine, Johns Hopkins University, Baltimore, Maryland., Austin RG; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Runyambo D; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Hish AJ; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Bartholf DeWitt S; Department of Pathology, Duke University Medical Center, Durham, North Carolina., George JT; Center for Theoretical Biological Physics, Rice University, Houston, Texas.; Department of Bioengineering, Rice University, Houston, Texas.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas., Kreulen RT; Department of Orthopedics, Duke University Medical Center, Durham, North Carolina., Boss MK; Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado., Lazarides AL; Department of Orthopedics, Duke University Medical Center, Durham, North Carolina., Kerr DL; Department of Orthopedics, Duke University Medical Center, Durham, North Carolina., Gerber DG; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Sivaraj D; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Armstrong AJ; Solid Tumor Program, Duke University Medical Center, Durham, North Carolina.; Duke Prostate Center, Duke University Medical Center, Durham, North Carolina., Dewhirst MW; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina., Eward WC; Department of Orthopedics, Duke University Medical Center, Durham, North Carolina., Levine H; Center for Theoretical Biological Physics, Rice University, Houston, Texas.; Department of Bioengineering, Rice University, Houston, Texas., Somarelli JA; Department of Medicine, Duke University Medical Center, Durham, North Carolina. jason.somarelli@duke.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2019 Jun; Vol. 17 (6), pp. 1391-1402. Date of Electronic Publication: 2019 Mar 12.
DOI:	10.1158/1541-7786.MCR-18-0763
Abstrakt:	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. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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