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

David Novo, Nikki Heath, Louise Mitchell, Giuseppina Caligiuri, Amanda MacFarlane, Dide Reijmer, Laura Charlton, John Knight, Monika Calka, Ewan McGhee, Emmanuel Dornier, David Sumpton, Susan Mason, Arnaud Echard, Kerstin Klinkert, Judith Secklehner, Flore Kruiswijk, Karen Vousden, Iain R. Macpherson, Karen Blyth, Peter Bailey, Huabing Yin, Leo M. Carlin, Jennifer Morton, Sara Zanivan and Jim C. Norman ()
Additional contact information
David Novo: Beatson Institute for Cancer Research
Nikki Heath: Beatson Institute for Cancer Research
Louise Mitchell: Beatson Institute for Cancer Research
Giuseppina Caligiuri: University of Glasgow
Amanda MacFarlane: Beatson Institute for Cancer Research
Dide Reijmer: Beatson Institute for Cancer Research
Laura Charlton: University of Glasgow
John Knight: Beatson Institute for Cancer Research
Monika Calka: University of Glasgow
Ewan McGhee: Beatson Institute for Cancer Research
Emmanuel Dornier: Beatson Institute for Cancer Research
David Sumpton: Beatson Institute for Cancer Research
Susan Mason: Beatson Institute for Cancer Research
Arnaud Echard: Institut Pasteur
Kerstin Klinkert: Institut Pasteur
Judith Secklehner: Beatson Institute for Cancer Research
Flore Kruiswijk: Beatson Institute for Cancer Research
Karen Vousden: Beatson Institute for Cancer Research
Iain R. Macpherson: Beatson Institute for Cancer Research
Karen Blyth: Beatson Institute for Cancer Research
Peter Bailey: University of Glasgow
Huabing Yin: University of Glasgow
Leo M. Carlin: Beatson Institute for Cancer Research
Jennifer Morton: Beatson Institute for Cancer Research
Sara Zanivan: Beatson Institute for Cancer Research
Jim C. Norman: Beatson Institute for Cancer Research

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07339-y

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