Piezo ion channels in cancer cell mechanotransduction
The mechanical dependence of transformation and metastasis is an emerging field, but the role of mechanosensitive channels has been largely omitted. This thesis focuses on the roles played by the mechanosensitive ion channels Piezo1 and Piezo2 in the transduction of mechanical stimuli (confinement,...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/664209 |
| Acceso en línea: | http://hdl.handle.net/10803/664209 |
| Access Level: | acceso abierto |
| Palabra clave: | Piezo Calcium Actin Metastasis Confinement Calci Actina Metàstasi Confinament 576 |
| Sumario: | The mechanical dependence of transformation and metastasis is an emerging field, but the role of mechanosensitive channels has been largely omitted. This thesis focuses on the roles played by the mechanosensitive ion channels Piezo1 and Piezo2 in the transduction of mechanical stimuli (confinement, adhesion, substrate rigidity, adhesive ligand concentration) by cancer cells. In a first chapter, we show that confinement triggers Piezo1-mediated calcium entry. This activates phosphodiesterase 1, reducing cAMP levels and, consequently, PKARac1 activity, relieving Myosin II from its inhibition. We also find a parallel, direct activation of Myosin II by confinement. As a combined result, cells stiffen and optimize their adhesion-free migration mode, usually responsible for in vivo migration during metastatic invasion. Piezo1 knockdown supresses confinement-induced calcium entry and impairs the underlying circuitry in ovarian epithelial (CHO) or melanoma (A375) cells. As a result, siPiezo1 cells show reduced migratory capacity under confinement. In the second chapter, we discover an essential role for Piezo2 as a transducer of environmental mechanical cues into RhoA activation to modulate the mechanobiological responses of MDA-MB-231-BrM2 brain metastatic breast cancer cells. Piezo2 knockdown disturbs stress fibre formation, adhesion orientation, force transmission and nuclear accumulation of the malignant co-transcriptional activator YAP, and this is phenocopied by extracellular calcium suppression. Promoting Actin polymerization with jasplakinolide or by over-expressing constitutively active forms of Rho or mDia1 restores stress fibres and nuclear YAP accumulation. In addition, Piezo2 knockdown disrupts several pro-metastatic functions: cell proliferation, migration, invadopodia formation, extracellular matrix degradation, and secretion of SERPINB2, a protein needed for protecting invasive cells from brain parenchymal defence mechanisms. The works presented in this thesis unveil important roles for Piezo channels as a first line of mechanical input detectors in distinct cells. These discoveries are relevant for several fields, e.g. cancer research, and highlight the importance of ion channels as transducers of environmental stimuli. |
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