1. Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism
- Author
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Séverine Marionneau-Lambot, Emeline Bon, Stefania Cannone, Sébastien Roger, Thibauld Oullier, Roseline Guibon, Maria Raffaella Greco, Rosa Rubino, Rosa Angela Cardone, Manuel Bernabe-Garcia, Gaëlle Fromont, Maria-Luisa Cayuela, Stephan J. Reshkin, Loredana Ciaccia, and Lorenzo Guerra
- Subjects
0301 basic medicine ,Scaffold protein ,Sodium-Hydrogen Exchangers ,PDZ domain ,Breast Neoplasms ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Animals ,Humans ,Neoplasm Invasiveness ,Vasculogenic mimicry ,Neoplasm Metastasis ,Phosphorylation ,Molecular Biology ,Zebrafish ,Sodium-Hydrogen Exchanger 1 ,Hydrogen-Ion Concentration ,Phosphoproteins ,Xenograft Model Antitumor Assays ,Phenotype ,Cell biology ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Molecular Medicine ,Female ,Mutant Proteins ,Signal transduction ,Reprogramming ,Signal Transduction - Abstract
Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism.
- Published
- 2019
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