Piezo1 activation attenuates thrombin-induced blebbing in breast cancer cells

Abstract

Cancer cells exploit a variety of migration modes to leave primary tumors and establish metastases, including amoeboid cell migration, which is typically reliant on bleb formation. Here we demonstrate that thrombin induces dynamic blebbing in the MDA-MB-231 breast cancer cell line, and confirm that PAR1 activation is sufficient to induce this effect. Cell confinement has been implicated as a driving force in bleb-based migration. Unexpectedly, we find that gentle contact compression, exerted using a custom built ‘cell press’ to mechanically stimulate cells, attenuated thrombin-induced blebbing. Thrombin-induced blebbing was similarly attenuated using Yoda1, an agonist of the mechanosensitive calcium channel Piezo1, and this attenuation was impaired in Piezo1 depleted cells. Additionally, Piezo1 activation suppressed thrombin-induced phosphorylation of ERM proteins, which are implicated in the blebbing process. Our results provide mechanistic insights into Piezo1 activation as a suppressor of dynamic blebbing, specifically that which is induced by thrombin.

The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling

“…We therefore exposed islet cells to two forms of mechanical stimulation, mild compression and fluid flow, while recording Ca 2+ concentration changes in the primary cilia by confocal microscopy. Compression was accomplished using the cell press ( O’Callaghan et al, 2022 ), a piezomotor-controlled manipulator that linearly translates a flexible polydimethylsiloxane (PDMS) compression pillar, which was fitted to the stage of the microscope. Using this device, we compressed islets expressing the cilia-targeted Ca 2+ indicator.…”

“…Islet compression experiments were performed with a custom-built manipulator referred to as the cell press ( O’Callaghan et al, 2022 ). The device consists of 3D-printed parts, a linear piezoelectric positioner (SLC-1730, SmarAct GmbH), which is operated through a MCS2 manual controller (SmarAct), and a PDMS compression pillar, which was cast from a 3D-printed mold.…”

Dendritic cell Piezo1 directs the differentiation of TH1 and Treg cells in cancer

“…Recent studies have suggested that Piezo1 is involved in regulating many of diseases, including the infectious inflammation and cancer ( Nguetse et al, 2020 ; Choi et al, 2019 ; Nonomura et al, 2018 ; Chang et al, 2019 ; Xie et al, 2022 ; Kuriyama et al, 2022 ; O’Callaghan et al, 2022 ; Liu et al, 2021 ). Piezo1 modulates macrophage polarization and stiffness sensing, which are related to calcium influx and the promotion of macrophage activation by actin ( Atcha et al, 2021 ).…”

Immunoregulatory Role of the Mechanosensitive Ion Channel Piezo1 in Inflammation and Cancer

“…Elimination of Piezo1 in myeloid cells could prevent cancer [42] Functional relevance of Piezo1 in cancer. In recent years, a number of studies have shown that Piezo1 plays an important role in regulating the occurrence and development of various tumors, such as stomach cancer [34], colon tumors [36], hepatocellular carcinoma [37], lung cancer [38,39], breast carcinoma [40], oral squamous cell carcinoma [41], and pancreatic ductal adenocarcinoma [42]. Table 2 shows various signaling pathways related to the induction of key regulators of Piezo1 channel proteins, in response to mechanical stimulation, which provides new research ideas for subsequent tumor treatment.…”

“…Piezo1 activation inhibits thrombin-induced phosphorylation of the ezrin, radixin, and moesin (ERM) proteins, which are involved in the foaming process. In the development of new drugs, Piezo1 activation could offer a novel way to inhibit thrombinase-induced blistering in breast cancer cells [40].…”