Probing mechanobiological role of filamin A in migration and invasion of human U87 glioblastoma cells using submicron soft pillars

Ketebo, Abdurazak Aman; Park, Chanyong; Kim, Jae-Won; Jun, Myeongjun; Park, Sungsu

doi:10.1186/s40580-021-00267-6

Cited by 9 publications

(4 citation statements)

References 53 publications

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“…11 At the molecular level, FlnA protein is involved in the response to mechanical stress, interacts with more than a hundred proteins and, thus, plays a role in mechanotransduction, migration, proliferation, morphology, and cell adhesion pathways. [12][13][14][15] Using conditional Flna Knock-Out (KO) mice developing MVD, we firstly highlighted an interplay between serotonin, transglutaminase 2 and FlnA that regulates the embryonic valve development, as well as activation of Erk signaling in these processes leading to MVD. 16,17 We also showed in vitro that FLNA-MVD mutations alter the interaction of FlnA with small-GTPase proteins (i.e.…”

Section: Introductionmentioning

confidence: 99%

Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model

Delwarde

Toquet

Aumond

et al. 2022

Cardiovascular Research

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Aims Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique Knock-In (KI) rat model for the FlnA-P637Q mutation associated-MVD. Methods and Results WT and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signaling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1 mm versus 1.8 ± 0.1, p = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% versus WT, p = 0.02). Histological analyses revealed a myxomatous remodeling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signaling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of TGF-β and inflammation in the disease. Conclusion The KI FlnA-P637Q rat model mimics human myxomatous mitral valve dystrophy, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, response to mechanical stress, and a central contribution of immune cells are highlighted as the main signaling pathways leading to myxomatous mitral valve dystrophy. Our findings pave the road to decipher underlying molecular mechanisms and the specific role of distinct cell populations in this context.

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Section: Introductionmentioning

confidence: 99%

Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model

Delwarde

Toquet

Aumond

et al. 2022

Cardiovascular Research

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“…[18,19] Furthermore, cell shape regulation during cell division was observed to be strongly impaired when 𝛼-actinin-4 is knocked down. [20,21] Moreover, cell migration and attachment to the extracellular matrix (ECM) require filamins [10,[22][23][24][25][26][27][28][29] and loss or mutation of filamins leads to developmental defects. [16,17,30,31] During their lifespan, cells need to undergo a sequence of shape changes for example, during cell division or tissue rearrangement.…”

Section: Introductionmentioning

confidence: 99%

“…[ 18,19 ] Furthermore, cell shape regulation during cell division was observed to be strongly impaired when α‐actinin‐4 is knocked down. [ 20,21 ] Moreover, cell migration and attachment to the extracellular matrix (ECM) require filamins [ 10,22–29 ] and loss or mutation of filamins leads to developmental defects. [ 16,17,30,31 ]…”

Section: Introductionmentioning

confidence: 99%

Twofold Mechanosensitivity Ensures Actin Cortex Reinforcement upon Peaks in Mechanical Tension

Ruffine,

Hartmann,

Frenzel

et al. 2023

Advanced Physics Research

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The actin cortex is an active polymer network underneath the plasma membrane at the periphery of mammalian cells. It is a major regulator of cell shape through the generation of active cortical tension. In addition, the cortex constitutes a mechanical shield that protects the cell during mechanical agitation. Cortical mechanics is tightly controlled by the presence of actin cross‐linking proteins that dynamically bind and unbind actin filaments. Cross‐linker actin bonds are weak non‐covalent bonds whose bond lifetime is likely affected by mechanical tension in the actin cortex making cortical composition inherently mechanosensitive. Here, a quantitative study of changes in cortex composition and turnover dynamics upon short‐lived peaks in active and passive mechanical tension in mitotic HeLa cells is presented. These findings dsclose a twofold mechanical reinforcement strategy of the cortex upon tension peaks entailing i) a direct catch‐bond mechanosensitivity of cross‐linkers filamin and α‐actinin and ii) an indirect cortical mechanosensitivity that triggers actin cortex reinforcement via enhanced polymerization of actin. Thereby a “molecular safety belt” mechanism that protects the cortex from injury upon mechanical challenges is disclosed.

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“…GTPases and several of their regulatory cofactors (Duval et al, 2014;Washington and Knecht, 2008). Because of its involvement facilitating cell adhesion and migration (Lamsoul et al, 2020), it is often associated with cancer invasion and metastasis (Ketebo et al, 2021;Zhang et al, 2014). In addition to interacting with Rho GTPases, FLNA has been described as a…”

Section: Erk/mapk Signaling Activationmentioning

confidence: 99%

The role of calcium ions in the leukemic bone marrow microenvironment

Pereira¹

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Leukemia is a cancer of the blood and bone marrow characterized by an uncontrolled proliferation and accumulation of abnormal white blood cells. Leukemia can be classified based on the course of the disease (acute or chronic) and the blood cell type involved (myeloid or lymphocytic), leading to four main subtypes: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Leukemia represents 2.5% of all new cancer cases per year, and survival rates in some leukemias remain low at 40%. The bone marrow microenvironment (BMM) is a system within the bone marrow comprising cellular and acellular components, all of which play a major role in hematopoiesis, providing the physical space where hematopoietic stem cells (HSCs) reside. The BMM interacts with HSCs, offering a “niche” for those cells and in case of leukemia, the BMM has a supportive role in disease maintenance and progression by supporting Leukemia stem cells (LSCs). One of the components of the BMM are calcium ions. Calcium is the most abundant mineral in the body, a key component of bones and is released by parathyroid hormone (PTH) induced bone remodeling. Calcium ions play a role in the localization, engraftment and adhesion of normal HSC to extracellular matrix (ECM) proteins in the BMM via the calcium sensing receptor (CaSR), thereby maintaining normal hematopoiesis. In addition of a major regulator of calcium homeostasis, CaSR contribute to the development of different cancers, functioning as either tumor suppressor or oncogene, depending on the involved tissue. However, the role of CaSR and its associated pathways in the local BMM for the development of leukemia is poorly understood. We hypothesized that calcium ions released from bone, subject to a fine balance between osteoblasts and osteoclasts, and/or CaSR, contribute to development, progression and response to therapy. We have shown that the local calcium concentration forms a gradient in the bone marrow niche and in mice with CML is similarly low as in control mice, but significantly higher in mice suffering from BCR ABL1 driven B ALL or MLL AF9 driven AML. Similarly, the calcium concentration in the human BMM was found to be higher in AML than in other leukemias. Regarding the function of calcium in leukemia cells, we found that AML and CML cells respond differently to calcium exposure, with AML cells exhibiting regulation of cellular processes such as adhesion to the ECM protein fibronectin and migration toward CXCL 12, whereas CML cells remained mostly unaltered. Using genetic deletion or overexpression of CaSR in murine models of leukemia, we observed that CaSR acts as tumor suppressor in BCR-ABL1 driven CML and B ALL and as oncogene in AML. Focusing on AML, our data shows that deficiency of CaSR on LICs leads, on one hand to increased apoptosis, and on the other hand to reduced cell cycle, reactive oxygen species (ROS) production and DNA damage in vivo, which may explain the observed prolongation of survival of mice. Complementary, in vitro experiments demonstrated that cells overexpressing CaSR have a distinct, cancer promoting phenotype compared to wildtype cells. Overexpression of CaSR led to an increase in proliferation, cell cycle, ROS production, DNA damage and reduced apoptosis. We have identified CaSR mediated pathways in AML and shown that CaSR enhances leukemia progression by activating MAPK/ERK and Wnt β catenin signaling. In addition, the CaSR interacting protein filamin A (FLNA) was shown to contribute to aggressive disease in vitro and in vivo. Furthermore, the mechanism underlying the role of CaSR in AML pathogenesis and possible regulation of LSCs was studied. Our findings demonstrated that CaSR ablation reduces myeloid progenitor function and proved that CaSR is required for maintenance of LSC pool by regulating its frequency and function. Further supporting the role of CaSR in LSC maintenance, genes associated with AML stemness and self renewal capacity were upregulated when CaSR was overexpressed and downregulated when CaSR was depleted. Given the role of CaSR in AML, the CaSR antagonist NPS 2143 was tested in vivo. The combination treatment of NPS 2143 with the standard of care, ara C, significantly reduced the tumor burden and prolonged the survival of mice with AML in syngeneic and xenotransplantation experiments. Based on the finding that CaSR functions as a tumor suppressor in CML, treatment of mice with the CaSR agonist cinacalcet in combination with imatinib prolonged survival of mice with CML compared to treatment with the mice given vehicle. Our results suggest that calcium ions stemming from the calcium-rich BMM via CaSR strongly and differentially influence leukemia progression. As an adjunct to existing treatment therapies, targeting of CaSR with specific pharmacologic antagonists may prolong survival of patients with AML.

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Probing mechanobiological role of filamin A in migration and invasion of human U87 glioblastoma cells using submicron soft pillars

Cited by 9 publications

References 53 publications

Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model

Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model

Twofold Mechanosensitivity Ensures Actin Cortex Reinforcement upon Peaks in Mechanical Tension

The role of calcium ions in the leukemic bone marrow microenvironment

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