Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels
| Autor: | Susan M. Mason, John R. P. Knight, Arnaud Echard, Giuseppina Caligiuri, Dide Reijmer, Monika Calka, Flore Kruiswijk, David Sumpton, David Novo, Karen Blyth, Iain R. Macpherson, Karen H. Vousden, Peter Bailey, Sara Zanivan, Kerstin Klinkert, Jim C. Norman, Judith Secklehner, Amanda MacFarlane, Nikki Heath, Huabing Yin, Jennifer P. Morton, Leo M. Carlin, Louise Mitchell, Ewan J. McGhee, Laura Charlton, Emmanuel Dornier |
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| Přispěvatelé: | The Beatson Institute for Cancer Research, University of Glasgow, Institute of Cancer Sciences [Glasgow, UK] (CR-UK Beatson Institute), James Watt School of Engineering [Univ Glasgow], Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Inflammation, Repair and Development, National Heart & Lung Institute, Imperial College London, Wolfson Wohl Cancer Research Centre [Glasgow, UK], University of Glasgow-Institute of Cancer Sciences [Glasgow, UK], 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)., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
[SDV]Life Sciences [q-bio] Mutant General Physics and Astronomy Exosomes Microscopy Atomic Force Extracellular matrix Mice chemistry.chemical_compound MESH: Animals MESH: Sialoglycoproteins MESH: Tumor Suppressor Protein p53 lcsh:Science MESH: Microscopy Atomic Force Multidisciplinary Manchester Cancer Research Centre biology Chemistry Cell biology Podocalyxin Female MESH: Sialomucins MESH: Mutation Sialomucins Endosome Sialoglycoproteins Science Integrin Mice Nude [SDV.CAN]Life Sciences [q-bio]/Cancer [SDV.BC]Life Sciences [q-bio]/Cellular Biology Exosome Article General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences MESH: Mice Nude Animals Humans MESH: Exosomes MESH: Mice Diacylglycerol kinase MESH: Humans ResearchInstitutes_Networks_Beacons/mcrc General Chemistry Microvesicles MESH: Cell Line MESH: rab GTP-Binding Proteins 030104 developmental biology rab GTP-Binding Proteins Mutation biology.protein lcsh:Q Tumor Suppressor Protein p53 MESH: Female |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-17 (2018) Nature Communications Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.5069. ⟨10.1038/s41467-018-07339-y⟩ Nature Communications, 2018, 9 (1), pp.5069. ⟨10.1038/s41467-018-07339-y⟩ 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 & Norman, J C 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 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-07339-y |
| Popis: | 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. Some p53 mutants promote invasive migration of cancer cells and metastasis of tumours in vivo. However the key mechanistic details behind these phenomena remain unclear. Here the authors propose a non-cell autonomous mechanism involving fibroblasts, whereby mutant p53-expressing cancer cells activate an exosome-mediated mechanism that influences integrin recycling in fibroblasts, thus influencing extracellular matrix remodelling to favour cancer cell invasion and migration. |
| Databáze: | OpenAIRE |
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