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; Jim C. Norman

doi:10.1038/s41467-018-07339-y

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 BlythPeter Bailey, Huabing Yin, Leo M. Carlin, Jennifer Morton, Sara Zanivan, Jim C. Norman

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	5069
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07339-y
Publication status	Published - 1 Dec 2018

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Manchester Cancer Research Centre

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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., ... Norman, J. C. (2018). Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nature Communications, 9(1), Article 5069. https://doi.org/10.1038/s41467-018-07339-y

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title = "Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels",

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{\textquoteright}s invasive/migratory gain-of-function by increasing RCP-dependent integrin recycling in other tumour cells. This process depends on mutp53{\textquoteright}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.",

author = "David Novo and Nikki Heath and Louise Mitchell and Giuseppina Caligiuri and Amanda MacFarlane and Dide Reijmer and Laura Charlton and John Knight and Monika Calka and Ewan McGhee and Emmanuel Dornier and David Sumpton and Susan Mason and Arnaud Echard and Kerstin Klinkert and Judith Secklehner and Flore Kruiswijk and Karen Vousden and Macpherson, {Iain R.} and Karen Blyth and Peter Bailey and Huabing Yin and Carlin, {Leo M.} and Jennifer Morton and Sara Zanivan and Norman, {Jim C.}",

note = "Funding Information: This work was funded by Cancer Research UK and Breast Cancer Now. We acknowledge the Cancer Research UK Glasgow Centre (C596/A18076) and the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07339-y",

language = "English",

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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, IR, Blyth, K, Bailey, P, Yin, H, Carlin, LM, Morton, J, Zanivan, S & Norman, JC 2018, 'Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels', Nature Communications, vol. 9, no. 1, 5069. https://doi.org/10.1038/s41467-018-07339-y

TY - JOUR

T1 - Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels

AU - Novo, David

AU - Heath, Nikki

AU - Mitchell, Louise

AU - Caligiuri, Giuseppina

AU - MacFarlane, Amanda

AU - Reijmer, Dide

AU - Charlton, Laura

AU - Knight, John

AU - Calka, Monika

AU - McGhee, Ewan

AU - Dornier, Emmanuel

AU - Sumpton, David

AU - Mason, Susan

AU - Echard, Arnaud

AU - Klinkert, Kerstin

AU - Secklehner, Judith

AU - Kruiswijk, Flore

AU - Vousden, Karen

AU - Macpherson, Iain R.

AU - Blyth, Karen

AU - Bailey, Peter

AU - Yin, Huabing

AU - Carlin, Leo M.

AU - Morton, Jennifer

AU - Zanivan, Sara

AU - Norman, Jim C.

N1 - Funding Information: This work was funded by Cancer Research UK and Breast Cancer Now. We acknowledge the Cancer Research UK Glasgow Centre (C596/A18076) and the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196). Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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

Abstract

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