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

Nikki Heath (1) , Louise Mitchell (1) , Giuseppina Caligiuri (2) , Amanda Macfarlane (1) , Dide Reijmer (1) , Laura Charlton (3) , John Knight (1) , Monika Calka (2) , Ewan Mcghee (1) , Emmanuel Dornier (1) , David Sumpton (1) , Susan Mason (1) , Arnaud Echard (4) , Kerstin Klinkert (4) , Judith Secklehner (2, 5) , Flore Kruiswijk (1) , Karen H. Vousden (1, 2) , Iain R Macpherson (1, 2) , Karen Blyth (1, 2) , Peter Bailey (6) , Huabing Yin (3) , Leo M Carlin (1, 5) , Jennifer Morton (1, 2) , Sara Zanivan (1, 2) , Jim C Norman (1, 2) , David Novo (1)

1 The Beatson Institute for Cancer Research
2 CR-UK Beatson Institute - Institute of Cancer Sciences [Glasgow, UK]
3 James Watt School of Engineering [Univ Glasgow]
4 Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division
5 Inflammation, Repair and Development, National Heart & Lung Institute
6 Wolfson Wohl Cancer Research Centre [Glasgow, UK]

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 podo-calyxin 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 micro-scopy 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.

Domaines: Biologie cellulaire; Sciences du Vivant [q-bio]; Cancer

Nikki Heath, Louise Mitchell, Giuseppina Caligiuri, Amanda Macfarlane, Dide Reijmer, et al.. Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nature Communications, 2018, 9 (1), pp.5069. ⟨10.1038/s41467-018-07339-y⟩. ⟨hal-02268889⟩