Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels

Novo, D. et al. (2018) Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nature Communications, 9, 5069. (doi: 10.1038/s41467-018-07339-y) (PMID:30498210) (PMCID:PMC6265295)

Abstract

Mutant p53s (mutp53) increase cancer invasiveness by upregulating Rab-coupling protein (RCP) and diacylglycerol kinase-α (DGKα)-dependent endosomal recycling. Here we report that mutp53-expressing tumour cells produce exosomes that mediate intercellular transfer of mutp53’s invasive/migratory gain-of-function by increasing RCP-dependent integrin recycling in other tumour cells. This process depends on mutp53’s ability to control production of the sialomucin, podocalyxin, and activity of the Rab35 GTPase which interacts with podocalyxin to influence its sorting to exosomes. Exosomes from mutp53-expressing tumour cells also influence integrin trafficking in normal fibroblasts to promote deposition of a highly pro-invasive extracellular matrix (ECM), and quantitative second harmonic generation microscopy indicates that this ECM displays a characteristic orthogonal morphology. The lung ECM of mice possessing mutp53-driven pancreatic adenocarcinomas also displays increased orthogonal characteristics which precedes metastasis, indicating that mutp53 can influence the microenvironment in distant organs in a way that can support invasive growth.

• Item Type: Articles
• Additional Information: Also supported by the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Yin, Professor Huabing and Zanivan, Professor Sara and Bailey, Dr Peter and Blyth, Professor Karen and Sumpton, Mr David and Kruiswijk, Dr Flore and MacPherson, Professor Iain and Norman, Professor James and Mitchell, Mrs Louise and Fontinha da Silva Novo, David and Caligiuri, Giuseppina and McGhee, Dr Ewan and Vousden, Karen and Morton, Professor Jen and Dornier, Mr Emmanuel Greg and Secklehner, Judith and Charlton, Ms Laura and Mason, Miss Susan and Carlin, Dr Leo
• Authors: Novo, D., Heath, N., Mitchell, L., Caligiuri, G., MacFarlane, A., Reijmer, D., Charlton, L., Knight, J., Calka, M., McGhee, E., Dornier, E., Sumpton, D., Mason, S., Echard, A., Klinkert, K., Secklehner, J., Kruiswijk, F., Vousden, K., Macpherson, I. R., Blyth, K., Bailey, P., Yin, H., Carlin, L. M., Morton, J., Zanivan, S., and Norman, J. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Science and Engineering > School of Engineering; College of Science and Engineering > School of Engineering > Biomedical Engineering
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Nature Communications 9: 5069
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
64798	4	CR-UK Centre renewal	Karen Vousden	Cancer Research UK (CRUK)	18076	RI CANCER SCIENCES