Mechanostimulation-induced integrin αvβ6 and latency associated peptide coupling activates TGF-β and regulates cancer metastasis and stemness

Dhawan, U. , Wang, W.-L., Lin, Y.-C., Yang, R.-B., Dalby, M. J. , Salmeron-Sanchez, M. and Yu, H.-h. (2023) Mechanostimulation-induced integrin αvβ6 and latency associated peptide coupling activates TGF-β and regulates cancer metastasis and stemness. Nano Today, 50, 101882. (doi: 10.1016/j.nantod.2023.101882)

Abstract

The existence of cancer stem cells is the single most important factor contributing to cancer recurrence, and despite immense therapeutic relevance, little research has been done on investigating their origin. Through mechanotransduction, cells translate biophysical cues to biochemical signals. However, little is known about its role in acquisition of cancer stem cell characteristics in non-stem cells. Here, highly ordered nanoenvironments are engineered as models to induce mechanotransduction in cancer cells and elucidate how cell environment delivers precise physical cues via mechanotransduction to modulate expression and localization of key mesenchymal markers to induce epithelial-mesenchymal transition (EMT) and regulate cancer stemness. By initiating integrin αVβ6 and Latency associated peptide (LAP) interactions, cell nanoenvironment mechanically activates TGF-β canonical and non-canonical signaling pathways and induces Epithelial-Mesenchymal transition in U2OS osteosarcoma cells. As a consequence of TGF-β mechanical activation, a synchronous regulation in cancer stem-cell and pluripotency biomarkers is also observed which transcends to formation of cell organoids, a characteristic of cancer stem cells. Furthermore, nanoenvironment-derived cells promote tumor growth and metastasis in-vivo. Mechanistically, RNA-sequencing, RNA-interference and protein translocation experiments establish that cell nanoenvironment plays a decisive role in imparting stemness abilities to incoming cells via EMT and reveals how cells can exploit mechanical sensing to orchestrate tumorigenicity.

• Item Type: Articles
• Additional Information: This study was supported by the Ministry of Science and Technology (MOST) of Taiwan (MOST-106–2628-M-001–001-MY3 and MOST-107–2627-M-001–007) and supported by the Academia Sinica Research Project on Nano Science and Technology and Academia Sinica Thematic Project. The study was also supported by the UK Engineering and Physical Sciences Research Council (EPSRC EP/P001114/1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Salmeron-Sanchez, Professor Manuel and Dalby, Professor Matthew and Dhawan, Dr Udesh
• Authors: Dhawan, U., Wang, W.-L., Lin, Y.-C., Yang, R.-B., Dalby, M. J., Salmeron-Sanchez, M., and Yu, H.-h.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Science and Engineering > School of Engineering > Biomedical Engineering
• Journal Name: Nano Today
• Publisher: Elsevier
• ISSN: 1748-0132
• ISSN (Online): 1878-044X
• Published Online: 28 May 2023
• Copyright Holders: Copyright © 2023 Elsevier Ltd.
• First Published: First published in Nano Today 50: 101882
• Publisher Policy: Reproduced in accordance with the publisher copyright policy

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
173192		Engineering growth factor microenvironments- a new therapeutic paradigm for regenerative medicine	Manuel Salmeron-Sanchez	Engineering and Physical Sciences Research Council (EPSRC)	EP/P001114/1	ENG - Biomedical Engineering