A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression

Chen, Xin; Wanggou, Siyi; Bodalia, Ankur; Zhu, Min; Dong, Weifan; Fan, Jerry J.; Yin, Weiqiang; Min, Hyun-Kee; Hu, Malini; Draghici, Diana; Dou, Wenkun; Li, Feng; Coutinho, Fiona J.; Whetstone, Heather; Kushida, Michelle; Dirks, Peter B.; Song, Yuanquan; Hui, Chi‐chung; Sun, Yu; Wang, Lu-Yang; Li, Xuejun; Huang, Xi

doi:10.1016/j.neuron.2018.09.046

Cited by 260 publications

(265 citation statements)

References 58 publications

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“…Furthermore, high Piezo1 expression was associated with vascular invasion and shorten survival time, indicating that Piezo1 could be associated with poor prognosis. Piezo1 has been confirmed to be associated with prognosis of several cancers, like breast cancer, glioma, and non-small cell lung cancer (Chen et al 2018;Huang et al 2019;Li et al 2015). Piezo1 was activated by Yoda1 that is an effective activator of Piezo1 channel (Syeda et al 2015), and highly expressed Piezo1 in HCT-116 and SW-480 cells was in negative association with cell viability; however, silencing Piezo1 suppressed colon cancer cell viability.…”

Section: Discussionmentioning

confidence: 99%

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

Sun

Liu

et al. 2020

J Cancer Res Clin Oncol

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Objective Increasing evidence has revealed that mechanical stress and elevated mechanical signals promote malignant tumor transformation and metastasis. This study aimed to explore the function of the mechanically activated ion-channel Piezo1 in the colon cancer metastasis and its potential regulatory mechanism. Methods First, we examined the expression levels of Piezo1 and mitochondrial calcium uniporter (MCU) both in colon cancer tissues and assessed the prognostic value of Piezo1 and MCU in a colon cancer cohort (n = 110). Second, functional assays were performed to investigate the effects of Piezo1 and MCU on colon cancer cell migration, invasion, and mitochondrial membrane potential. Third, we analyzed the expression of Piezo1, MCU, and HIF-1α by overexpressing/silencing each other's expression. Results We found that Piezo1 was up-regulated and MCU was down-regulated in colon cancer tissues. Piezo1 and MCU were both correlated with poor prognosis of patients with colon cancer. Overexpressing Piezo1 and silencing MCU could promote colon cancer cell migration and metastasis, reduce mitochondrial membrane potential, and promote each other's expression. We also found that HIF-1α was up-regulated in colon cancer tissues. Additionally, silencing Piezo1 inhibited the expression of HIF-1α and VEGF, which was contrary to MCU silencing. Intriguingly, Piezo1-overexpressing cells did not regain their migration behaviors when HIF-1α expression was inhibited, which was accompanied with the re-expression of MCU and VEGF. Conclusion In our study, Piezo1 is involved in colon cancer cell metastasis. Furthermore, our findings indicated a possible Piezo1-MCU-HIF-1α-VEGF axis, which still need further exploration.Keywords Colon cancer · Metastasis · Piezo1 · Mitochondrial calcium uniporter · HIF-1α Yanhua Sun and Ming Li have contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

Sun

Liu

et al. 2020

J Cancer Res Clin Oncol

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“…The ability to genetically manipulate and observe border cell migration in its native tissue environment in real time makes it a powerful tool for identifying conserved regulators of collective invasion in development and in cancer 29,31,32 . Moreover, the use of the Drosophila system has also recently been leveraged for studies to identify conserved molecular mechanisms that drive GBM cell proliferation, survival, and self-renewal 33,34,35,36,37 .…”

Section: Introductionmentioning

confidence: 99%

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Volovetz

Berezovsky

Alban

et al. 2019

Preprint

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Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development.Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs. RAP1A

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“…Despite its clear physiological importance, the mechanisms by which cell-generated mechanical forces act to activate Piezo1 remain essentially unknown, either in hNSPCs or any other cell type. Uncovering how traction forces activate Piezo1 is vital to understanding the channel's role in stem cell fate 7 , cell migration 13,33 , and cancer 12,34 .…”

Section: Introductionmentioning

confidence: 99%

Myosin-II mediated traction forces evoke localized Piezo1 Ca²⁺ flickers

Ellefsen

Chang

Nourse

et al. 2018

Preprint

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Piezo channels transduce mechanical stimuli into electrical and chemical signals, and in doing so, powerfully influence development, tissue homeostasis, and regeneration. While much is known about how Piezo1 responds to external forces, its response to internal, cell-generated forces remains poorly understood. Here, using measurements of endogenous Piezo1 activity and traction forces in native cellular conditions, we show that actomyosin-based cellular traction forces generate spatially-restricted Ca 2+ flickers in the absence of externally-applied mechanical forces. Although Piezo1 channels diffuse readily in the plasma membrane and are widely distributed across the cell, their flicker activity is enriched in regions proximal to force-producing adhesions. The mechanical force that activates Piezo1 arises from Myosin II phosphorylation by Myosin Light Chain Kinase. We propose that Piezo1 Ca 2+ flickers allow spatial segregation of mechanotransduction events, and that diffusion allows channel molecules to efficiently respond to transient, local mechanical stimuli. Movie M1. Piezo1 Ca 2+ flickers are reduced in Piezo1-knockout HFFs. The movie shows an F/F 0 ratio movie of Ca 2+ flickers from WT and Piezo1-KO HFFs. Movie M2. Piezo1 Ca 2+ flickers are reduced in Piezo1-knockout MEFs. The movie shows an F/F 0 ratio movie of Ca 2+ flickers from WT and Piezo1-KO MEFs. Movie M3. Piezo1 Ca 2+ flickers imaged from HFFs. The movie shows the F/F 0 ratio movie from WT HFFs that was used for localization of Piezo1 Ca 2+ flickers in Fig. S2. Movie M4. Mobility of Piezo1-tdTomato puncta in mNSPCs imaged using TIRFM. Puncta visible outside the yellow cell line are from neighboring cells.

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A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression

Cited by 260 publications

References 58 publications

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Myosin-II mediated traction forces evoke localized Piezo1 Ca²⁺ flickers

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A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression

Cited by 260 publications

References 58 publications

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Myosin-II mediated traction forces evoke localized Piezo1 Ca2+ flickers

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Myosin-II mediated traction forces evoke localized Piezo1 Ca²⁺ flickers