Direct evidence for cell adhesion-mediated radioresistance (CAM-RR) on the level of individual integrin β1 clusters

Babel, Laura; Grunewald, Miriam; Lehn, Robert; Langhans, Markus; Meckel, Tobias

doi:10.1038/s41598-017-03414-4

Cited by 15 publications

(18 citation statements)

References 57 publications

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“…Cell fixation and antibody staining were performed as described earlier ( 19 ). In brief, Jurkat cells were fixed with a rapid and complete immobilization fixation protocol optimized for membrane proteins ( 20 ).…”

Section: Methodsmentioning

confidence: 99%

Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

et al. 2018

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Impairment or stimulation of the immune system by ionizing radiation (IR) impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL) to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naïve T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca2+, an upregulation of CD25 surface expression, interleukin-2 and interferon-γ synthesis, elevated expression of Ca2+ sensitive K+ channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca2+ buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca2+-dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients.

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Section: Methodsmentioning

confidence: 99%

Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

et al. 2018

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“…The results of these experiments are well in line with our previous findings in that not only integrin β1 clustering, but also the number of the immediate downstream signaling partner pFAK (phosphorylated focal adhesion kinase) differs significantly between the cultured conditions. 2D cultured cells presumably possess an impaired signalling efficiency [ 5 ]. At this point we can conclude that the localization and organization of cholesterol rafts differ in cells depending on whether they were cultured in 2D or 3D.…”

Section: Main Textmentioning

confidence: 99%

“…In contrast, the same IR dose turned out to be completely ineffective in 3D cultured cells for affecting the well clustered organization of integrins. Also a high dose of irradiation (15 Gy) leads in 2D cultured cells to a complete break down of integrin clusters while it causes only a partial disintegration in 3D cultured cells [ 5 ].…”

Section: Main Textmentioning

confidence: 99%

“…This phenomenon of increased radioresistance in a 3D matrix has been termed cell-adhesion-mediated-radio-resistance (CAM-RR) [ 1 – 3 ]. We recently found that clustering of integrin β1 is a sensitive and robust indicator of radio-resistance [ 5 ]. Cells cultured under standard (2D) conditions are not able to organize integrin receptors, which facilitate cell adhesion [ 4 ], into firm and stable clusters.…”

Section: Introductionmentioning

confidence: 99%

“…The same treatment has no perceivable effect on the well clustered organization of integrins in 3D cultured cells. On the basis of these data we could therefore causally link the radioresistance of 3D cells to their ability to maintain stable clusters [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Lipid-rafts remain stable even after ionizing radiation induced disintegration of β1 integrin containing focal adhesions

et al. 2017

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ObjectiveAdhesion of cells to the extracellular matrix is facilitated by integrin receptors. We recently found that a nanoscale organization of plasma membrane located integrins containing the β1 subunit is responsible for an enhanced radio-resistance in 3D cultured cells over cells grown in 2D. While ionizing radiation is known to have broad effects on the lipid composition of the plasma membrane and their organization in lipid-rafts, it is not clear whether the effects of ionizing radiation on the nanoscale clustering of integrins is lipid-raft dependent.ResultsUsing single molecule microscopy we can show that β1 integrins colocalize with cholesterol in lipid-rafts. Ionizing radiation, as an extrinsic stressor, causes the separation of β1 integrins from cholesterol lipid raft suggesting that the effects of ionizing radiation on the clustering of β1 integrins are lipid-raft independent.Electronic supplementary materialThe online version of this article (10.1186/s13104-017-3032-8) contains supplementary material, which is available to authorized users.

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Human Platelet Lysates‐Based Hydrogels: A Novel Personalized 3D Platform for Spheroid Invasion Assessment

et al. 2020

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Fundamental physiologic and pathologic phenomena such as wound healing and cancer metastasis are typically associated with the migration of cells through adjacent extracellular matrix. In recent years, advances in biomimetic materials have supported the progress in 3D cell culture and provided biomedical tools for the development of models to study spheroid invasiveness. Despite this, the exceptional biochemical and biomechanical properties of human‐derived materials are poorly explored. Human methacryloyl platelet lysates (PLMA)‐based hydrogels are herein proposed as reliable 3D platforms to sustain in vivo‐like cell invasion mechanisms. A systematic analysis of spheroid viability, size, and invasiveness is performed in three biomimetic materials: PLMA hydrogels at three different concentrations, poly(ethylene glycol) diacrylate, and Matrigel. Results demonstrate that PLMA hydrogels perfectly support the recapitulation of the tumor invasion behavior of cancer cell lines (MG‐63, SaOS‐2, and A549) and human bone‐marrow mesenchymal stem cell spheroids. The distinct invasiveness ability of each cell type is reflected in the PLMA hydrogels and, furthermore, different mechanical properties produce an altered invasive behavior. The herein presented human PLMA‐based hydrogels could represent an opportunity to develop accurate cell invasiveness models and open up new possibilities for humanized and personalized high‐throughput screening and validation of anticancer drugs.

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Direct evidence for cell adhesion-mediated radioresistance (CAM-RR) on the level of individual integrin β1 clusters

Cited by 15 publications

References 57 publications

Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

Lipid-rafts remain stable even after ionizing radiation induced disintegration of β1 integrin containing focal adhesions

Human Platelet Lysates‐Based Hydrogels: A Novel Personalized 3D Platform for Spheroid Invasion Assessment

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