Collagen VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche

Papalazarou, V., Drew, J., Juin, A., Spence, H. J., Whitelaw, J., Nixon, C., Salmeron-Sanchez, M. and Machesky, L. M. (2022) Collagen VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche. Journal of Cell Science, 135(24), jcs259978. (doi: 10.1242/jcs.259978) (PMID:36546396) (PMCID:PMC9845737)

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Abstract

Pancreatic cancer is a deadly and highly metastatic disease, although how metastatic lesions establish is not fully understood. A key feature of pancreatic tumours is extensive fibrosis and deposition of extracellular matrix (ECM). While pancreatic cancer cells are programmed by stimuli derived from a stiff ECM, metastasis requires loss of attachment and adaptation to a softer microenvironment at distant sites. Growing evidence suggests that stiff ECM influences pancreatic cancer cell behaviour. Here, we argue that this influence is reversible and that pancreatic cancer cells can be reprogrammed upon sensing soft substrates. Using engineered polyacrylamide hydrogels with tuneable mechanical properties, we show that collagen VI is specifically upregulated in pancreatic cancer cells on soft substrates, due to a lack of integrin engagement. Furthermore, the expression of collagen VI is inversely correlated with mechanosensing and activity of YAP (also known as YAP1), which might be due to a direct or indirect effect on transcription of genes encoding collagen VI. Collagen VI supports migration in vitro and metastasis formation in vivo. Metastatic nodules formed by pancreatic cancer cells lacking Col6a1 display stromal cell-derived collagen VI deposition, suggesting that collagen VI derived from either cancer cells or the stroma is an essential component of the metastatic niche.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Salmeron-Sanchez, Professor Manuel and Nixon, Mr Colin and Machesky, Professor Laura and Juin, Dr Amelie and Whitelaw, Mr Jamie and Spence, Dr Heather and Papalazarou, Vasileios
Authors: Papalazarou, V., Drew, J., Juin, A., Spence, H. J., Whitelaw, J., Nixon, C., Salmeron-Sanchez, M., and Machesky, L. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Journal of Cell Science
Publisher:Company of Biologists
ISSN:0021-9533
ISSN (Online):1477-9137
Published Online:22 December 2022
Copyright Holders:Copyright © 2022 The Company of Biologists Ltd
First Published:First published in Journal of Cell Science 135(24): jcs259978
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190874CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076Institute of Cancer Sciences
173192Engineering growth factor microenvironments- a new therapeutic paradigm for regenerative medicineManuel Salmeron-SanchezEngineering and Physical Sciences Research Council (EPSRC)EP/P001114/1ENG - Biomedical Engineering