Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition

Datta, A., Sandilands, E., Mostov, K. E. and Bryant, D. M. (2017) Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition. Cellular Signalling, 40, pp. 91-98. (doi: 10.1016/j.cellsig.2017.09.001) (PMID:28888686)

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The formation of lumens in epithelial tissues requires apical-basal polarization of cells, and the co-ordination of this individual polarity collectively around a contiguous lumen. Signals from the Extracellular Matrix (ECM) instruct epithelia as to the orientation of where basal, and thus consequently apical, surfaces should be formed. We report that this pathway is normally absent in Calu-3 human lung adenocarcinoma cells in 3-Dimensional culture, but that paracrine signals from MRC5 lung fibroblasts can induce correct orientation of polarity and acinar morphogenesis. We identify HGF, acting through the c-Met receptor, as the key polarity-inducing morphogen, which acts to activate β1-integrin-dependent adhesion. HGF and ECM-derived integrin signals co-operate via a c-Src-dependent inhibition of the RhoA-ROCK1 signalling pathway via p190A RhoGAP. This occurred via controlling localization of these signalling pathways to the ECM-abutting surface of cells in 3-Dimensional culture. Thus, stromal derived signals can influence morphogenesis in epithelial cells by controlling activation and localization of cell polarity pathways.

Item Type:Articles
Additional Information:Supported by NIH grants R01DK074398, R01DK091530 and 2P50 GM081879 (KM), and K99CA163535 (DB).
Glasgow Author(s) Enlighten ID:Bryant, Dr David and Sandilands, Dr Emma
Authors: Datta, A., Sandilands, E., Mostov, K. E., and Bryant, D. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cellular Signalling
ISSN (Online):1873-3913
Published Online:06 September 2017
Copyright Holders:Copyright © 2017 Elsevier Inc.
First Published:First published in Cellular Signalling 40:91-98
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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