TAMI-60. MODULATION OF CELL BIOMECHANICS THROUGH GUIDANCE RECEPTOR PLEXIN-B2 FACILITATES GLIOBLASTOMA INFILTRATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi210-vi211
Author(s):  
Roland Friedel ◽  
Yong Huang ◽  
Rut Tejero ◽  
Chrystian Junqueira Alves ◽  
Concetta Brusco ◽  
...  
Keyword(s):  
Biomechanical Properties ◽  
Cellular Level ◽  
Brain Parenchyma ◽  
Tumor Spread ◽  
Cell Biomechanics ◽  
Fiber Tracts ◽  
Downstream Effectors ◽  
Cellular Biomechanics ◽  
Stem Cell Lines ◽  
Mechanical Dynamics

Abstract Infiltrative growth is a major cause of the high lethality of malignant brain tumors such as glioblastoma (GBM). The study of the contribution of biomechanical processes to GBM invasion is an emerging field. We show here that GBM cells upregulate the guidance receptor Plexin-B2 to gain invasiveness by modulating their biomechanical properties. Deletion of Plexin-B2 in GBM stem cells limited tumor spread and shifted invasion paths from axon fiber tracts to perivascular routes. On a cellular level, Plexin-B2 adjusts cell adhesiveness, migratory responses to different matrix stiffness, and actomyosin dynamics, thus empowering GBM cells to leave stiff tumor bulk and infiltrate softer brain parenchyma. Correspondingly, gene signatures affected by Plexin-B2 were associated with locomotor regulation, matrix interactions, and cellular biomechanics. On a molecular level, the intracellular Ras-GAP domain contributed to Plexin-B2 function, while the signaling relationship with downstream effectors Rap1/2 appeared variable between GBM stem cell lines, reflecting intertumoral heterogeneity. Our studies have established Plexin-B2 as a modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness. Ongoing investigations focus on the regulation of the biomechanical properties of cell membrane and cell actomyosin cortex through plexins that provide GBM cells with the mechanical dynamics to penetrate to restricted space.

scholarly journals Plexin-B2 facilitates glioblastoma infiltration by modulating cell biomechanics

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yong Huang ◽  
Rut Tejero ◽  
Vivian K. Lee ◽  
Concetta Brusco ◽  
Theodore Hannah ◽  
...  
Keyword(s):  
Cellular Level ◽  
Brain Parenchyma ◽  
Matrix Stiffness ◽  
Tumor Spread ◽  
Cell Biomechanics ◽  
Fiber Tracts ◽  
Downstream Effectors ◽  
Cellular Biomechanics ◽  
Matrix Interactions ◽  
Stem Cell Lines

AbstractInfiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM). We show here that GBM cells upregulate guidance receptor Plexin-B2 to gain invasiveness. Deletion of Plexin-B2 in GBM stem cells limited tumor spread and shifted invasion paths from axon fiber tracts to perivascular routes. On a cellular level, Plexin-B2 adjusts cell adhesiveness, migratory responses to different matrix stiffness, and actomyosin dynamics, thus empowering GBM cells to leave stiff tumor bulk and infiltrate softer brain parenchyma. Correspondingly, gene signatures affected by Plexin-B2 were associated with locomotor regulation, matrix interactions, and cellular biomechanics. On a molecular level, the intracellular Ras-GAP domain contributed to Plexin-B2 function, while the signaling relationship with downstream effectors Rap1/2 appeared variable between GBM stem cell lines, reflecting intertumoral heterogeneity. Our studies establish Plexin-B2 as a modulator of cell biomechanics that is usurped by GBM cells to gain invasiveness.

scholarly journals NIMG-21. FROM BEYOND THE MARGIN: HIGH ANGULAR RESOLUTION Q-SPACE MRI MAY DETECT GLIOBLASTOMA TUMOR CELL INVASION INTO BRAIN PARENCHYMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi166-vi166
Author(s):  
Owen Leary ◽  
Steven Toms ◽  
John Zepecki ◽  
Derek Merck ◽  
Nikos Tapinos ◽  
...  
Keyword(s):  
Xenograft Model ◽  
B Value ◽  
Brain Parenchyma ◽  
High Angular Resolution ◽  
Imaging Data ◽  
Tumor Spread ◽  
Diffusion Weighted ◽  
Mri Sequences ◽  
Mitochondrial Antibody ◽  
Weighted Sequences

Abstract BACKGROUND Invasion of glioblastoma tumor cells beyond the visible margins is hypothesized to mediate tumor spread and recurrence, and thereby affect poor survival. Radiomic biomarkers associated with the extent of tumor infiltration are virtually non-existent. METHODS Seven subjects diagnosed with glioblastoma underwent high resolution “Q-Space” diffusion-weighted MRI sequences (Siemens 3T scanner, 64 gradient directions, b-value=1000s/mm2) during pre-operative MRI workup. For each subject, the largest tumor was manually segmented, and patterns of probabilistic inter-voxel coherence intersecting each segmentation generated as tractograms using DSI Studio (length=0–200mm, AT=30º). Separately, immunodeficient (Nu/J) mice were injected sub-hippocampally with patient-derived glioma stem cells (GSCs) using stereotactic guidance. Two months after injection, mice were sacrificed, resected brains were scanned on a Bruker 7T MRI using cryoprobe with T2-weighted and diffusion-weighted sequences (512 directions), and tumor-intersecting tractography displayed. 3D whole-brain reconstruction of the same xenograft model, stained with anti-human mitochondrial antibody, was performed for comparison. In one patient undergoing resection of fronto-temporal glioblastoma, BrainLab intraoperative navigation was used for stereotactic biopsy of extra-tumor parenchymal samples localized according to proximity to tumor-intersecting tractography. RNA-seq was performed on all samples using Illumina HiSeq2500 by a blinded analyst. RESULTS All human tumors (n=7) displayed region-specific long projecting tracts extending into brain parenchyma (Mean=23.2mm, SD=3.1mm). Maximum tract length varied from 80–130mm (Mean=102mm, SD=20.4mm). Xenograft models displayed similar tumor-intersecting tractography (n=3), with 3D reconstruction of stained GSCs replicating that pattern. RNAseq data revealed significant overrepresentation (≥2-fold) of 528 transcripts in projecting tumor tract-associated samples compared to samples obtained from the tumor mass itself and brain parenchyma unassociated with projecting tumor tracts. Functional classification revealed that 62% of these transcripts regulate cell motility as part of inter-related networks. CONCLUSION These imaging data, backed by region-specific transcriptomic evidence, suggest that Q-Space MRI may discriminate localizable patterns of inter-voxel coherence representing tumor-associated infiltration pathways in glioblastoma.

scholarly journals ERK3-MK5 signaling regulates myogenic differentiation and muscle regeneration by promoting FoxO3 degradation

2021 ◽  
Author(s):  
Mathilde Soulez ◽  
Pierre-Luc Tanguay ◽  
Florence Dô ◽  
Colin Crist ◽  
Junio Dort ◽  
...  
Keyword(s):  
Muscle Regeneration ◽  
Myogenic Differentiation ◽  
Muscle Growth ◽  
Ectopic Expression ◽  
Cellular Level ◽  
Mitogen Activated Protein Kinase ◽  
Primary Myoblasts ◽  
Downstream Effectors ◽  
Mitogen Activated Protein ◽  
Control Post

ABSTRACTThe physiological functions and downstream effectors of the atypical mitogen-activated protein kinase ERK3 remain to be characterized. We recently reported that mice expressing catalytically-inactive ERK3 (Mapk6KD/KD) exhibit a reduced post-natal growth rate as compared to control mice. Here, we show that genetic inactivation of ERK3 impairs post-natal skeletal muscle growth and adult muscle regeneration after injury. Loss of MK5 phenocopies the muscle phenotypes of Mapk6KD/KD mice. At the cellular level, genetic or pharmacological inactivation of ERK3 or MK5 induces precocious differentiation of C2C12 or primary myoblasts, concomitant with MyoD activation. Reciprocally, ectopic expression of activated MK5 inhibits myogenic differentiation. Mechanistically, we show that MK5 directly phosphorylates FoxO3, promoting its degradation and reducing its association with MyoD. Depletion of FoxO3 rescues in part the premature differentiation of C2C12 myoblasts observed upon inactivation of ERK3 or MK5. Our findings reveal that ERK3 and its substrate MK5 act in a linear signaling pathway to control post-natal myogenic differentiation.

In Situ Calcium Signaling of Chondrocytes Under Non-Serum and Serum Culture

2013 ◽  
Author(s):  
Yilu Zhou ◽  
Lauren Resutek ◽  
Liyun Wang ◽  
X. Lucas Lu
Keyword(s):  
Calcium Signaling ◽  
Mechanical Stimulation ◽  
Biomechanical Properties ◽  
Cellular Level ◽  
Cartilage Explants ◽  
Serum Free ◽  
Better Than

Chemically defined serum-free medium has been shown to maintain the mechanical properties of cartilage allografts better than serum supplemented medium during long-term in vitro culture [1]. Little is known about this beneficial mechanism at a cellular level. Intracellular calcium ([Ca2+]i) signaling is one of the earliest responses in chondrocytes under mechanical stimulation [2]. It was recently found that calcium signaling is involved in the regulation of chondrocyte morphology changes and its short-term anabolic and catabolic responses under mechanical stimulation [3]. In this study we hypothesized that the beneficial mechanisms of serum-free culture could be indicated by the spatiotemporal features of [Ca2+]i signaling of chondrocytes in situ. We aimed to: (i) compare the in situ spontaneous [Ca2+]i responses of chondrocytes cultured in medium with and without serum; (ii) investigate the correlation between the [Ca2+]i responses of chondrocytes and the biomechanical properties of cartilage explants.

scholarly journals Biology and Biomechanics of the Heart Valve Extracellular Matrix

2020 ◽  
Vol 7 (4) ◽  
pp. 57
Author(s):  
Karthik M. Kodigepalli ◽  
Kaitlyn Thatcher ◽  
Toni West ◽  
Daniel P. Howsmon ◽  
Frederick J. Schoen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Heart Valve ◽  
Heart Valves ◽  
Biomechanical Properties ◽  
Cellular Level ◽  
Risk Patients ◽  
Pediatric Populations ◽  
Dynamic Structures ◽  
Functional Movements

Heart valves are dynamic structures that, in the average human, open and close over 100,000 times per day, and 3 × 109 times per lifetime to maintain unidirectional blood flow. Efficient, coordinated movement of the valve structures during the cardiac cycle is mediated by the intricate and sophisticated network of extracellular matrix (ECM) components that provide the necessary biomechanical properties to meet these mechanical demands. Organized in layers that accommodate passive functional movements of the valve leaflets, heart valve ECM is synthesized during embryonic development, and remodeled and maintained by resident cells throughout life. The failure of ECM organization compromises biomechanical function, and may lead to obstruction or leaking, which if left untreated can lead to heart failure. At present, effective treatment for heart valve dysfunction is limited and frequently ends with surgical repair or replacement, which comes with insuperable complications for many high-risk patients including aged and pediatric populations. Therefore, there is a critical need to fully appreciate the pathobiology of biomechanical valve failure in order to develop better, alternative therapies. To date, the majority of studies have focused on delineating valve disease mechanisms at the cellular level, namely the interstitial and endothelial lineages. However, less focus has been on the ECM, shown previously in other systems, to be a promising mechanism-inspired therapeutic target. Here, we highlight and review the biology and biomechanical contributions of key components of the heart valve ECM. Furthermore, we discuss how human diseases, including connective tissue disorders lead to aberrations in the abundance, organization and quality of these matrix proteins, resulting in instability of the valve infrastructure and gross functional impairment.

scholarly journals Biomechanics of subcellular structures by non-invasive Brillouin microscopy

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Giuseppe Antonacci ◽  
Sietse Braakman
Keyword(s):  
Mechanical Response ◽  
Single Cells ◽  
Three Dimensional ◽  
Biomechanical Properties ◽  
Cell Stiffness ◽  
Non Invasive ◽  
Cellular Biomechanics ◽  
Latrunculin A ◽  
Longitudinal Elastic Modulus ◽  
A Cell

Abstract Cellular biomechanics play a pivotal role in the pathophysiology of several diseases. Unfortunately, current methods to measure biomechanical properties are invasive and mostly limited to the surface of a cell. As a result, the mechanical behaviour of subcellular structures and organelles remains poorly characterised. Here, we show three-dimensional biomechanical images of single cells obtained with non-invasive, non-destructive Brillouin microscopy with an unprecedented spatial resolution. Our results quantify the longitudinal elastic modulus of subcellular structures. In particular, we found the nucleoli to be stiffer than both the nuclear envelope (p < 0.0001) and the surrounding cytoplasm (p < 0.0001). Moreover, we demonstrate the mechanical response of cells to Latrunculin-A, a drug that reduces cell stiffness by preventing cytoskeletal assembly. Our technique can therefore generate valuable insights into cellular biomechanics and its role in pathophysiology.

scholarly journals Glioma infiltration of the corpus callosum: early signs detected by DTI

2013 ◽  
Vol 112 (2) ◽  
pp. 217-222 ◽  
Author(s):  
K. Kallenberg ◽  
T. Goldmann ◽  
J. Menke ◽  
H. Strik ◽  
H. C. Bock ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Corpus Callosum ◽  
Diffusion Tensor ◽  
Brain Parenchyma ◽  
Contralateral Hemisphere ◽  
Tumor Spread ◽  
Conventional Mri ◽  
Apparent Diffusion ◽  
Adc Values ◽  
Histopathological Studies

Abstract The most frequent primary brain tumors, anaplastic astrocytomas (AA) and glioblastomas (GBM): tend to invasion of the surrounding brain. Histopathological studies found malignant cells in macroscopically unsuspicious brain parenchyma remote from the primary tumor, even affecting the contralateral hemisphere. In early stages, diffuse interneural infiltration with changes of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is suspected. The purpose of this study was to investigate the value of DTI as a possible instrument of depicting evidence of tumor invasion into the corpus callosum (CC). Preoperatively, 31 patients with high-grade brain tumors (8 AA and 23 GBM) were examined by MRI at 3 T, applying a high-resolution diffusion tensor imaging (DTI) sequence. ADC- and FA-values were analyzed in the tumor-associated area of the CC as identified by fiber tracking, and were compared to matched healthy controls. In (MR-)morphologically normal appearing CC the ADC values were elevated in the tumor patients (n = 22; 0.978 × 10−3 mm²/s) compared to matched controls (0.917 × 10−3 mm²/s, p < 0.05), and the corresponding relative FA was reduced (rFA: 88 %, p < 0.01). The effect was pronounced in case of affection of the CC visible on MRI (n = 9; 0.978 × 10−3 mm²/s, p < 0.05; rFA: 72 %, p < 0.01). Changes in diffusivity and anisotropy in the CC can be interpreted as an indicator of tumor spread into the contralateral hemisphere not visible on conventional MRI.

Multimode light microscopy and fluorescence-based reagents as tools for the study of chemical and molecular dynamics of living cells and tissues

1992 ◽  
Vol 50 (1) ◽  
pp. 418-419
Author(s):  
D. L. Taylor
Keyword(s):  
Living Cells ◽  
Cellular Level ◽  
Molecular Techniques ◽  
Cellular Functions ◽  
Macromolecular Assemblies ◽  
Cell Functions ◽  
Molecular Events ◽  
Yield Information ◽  
Full Knowledge ◽  
Structural Methods

Cells function through the complex temporal and spatial interplay of ions, metabolites, macromolecules and macromolecular assemblies. Biochemical approaches allow the investigator to define the components and the solution chemical reactions that might be involved in cellular functions. Static structural methods can yield information concerning the 2- and 3-D organization of known and unknown cellular constituents. Genetic and molecular techniques are powerful approaches that can alter specific functions through the manipulation of gene products and thus identify necessary components and sequences of molecular events. However, full knowledge of the mechanism of particular cell functions will require direct measurement of the interplay of cellular constituents. Therefore, there has been a need to develop methods that can yield chemical and molecular information in time and space in living cells, while allowing the integration of information from biochemical, molecular and genetic approaches at the cellular level.

Gap junctions in the prothoracic glands of the tobacco hornworm, Manduca sexta

1992 ◽  
Vol 50 (1) ◽  
pp. 706-707
Author(s):  
Ji-da Dai ◽  
M. Joseph Costello ◽  
Lawrence I. Gilbert
Keyword(s):  
Gap Junctions ◽  
Small Molecules ◽  
Manduca Sexta ◽  
Freeze Fracture ◽  
Cell Communication ◽  
Cellular Level ◽  
Thin Sections ◽  
Prothoracic Glands ◽  
Polyhydroxylated Steroids ◽  
Stimulation Of

Insect molting and metamorphosis are elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands (PGs). Prothoracicotropic hormone stimulation of steroidogenesis by the PGs at the cellular level involves both calcium and cAMP. Cell-to-cell communication mediated by gap junctions may play a key role in regulating signal transduction by controlling the transmission of small molecules and ions between adjacent cells. This is the first report of gap junctions in the PGs, the evidence obtained by means of SEM, thin sections and freeze-fracture replicas.

Biomedical applications: Pitfalls in the practice

1994 ◽  
Vol 52 ◽  
pp. 378-379
Author(s):  
J. D. Shelburne ◽  
Peter Ingram ◽  
Victor L. Roggli ◽  
Ann LeFurgey
Keyword(s):  
Operating Room ◽  
Liquid Nitrogen ◽  
Lung Tissue ◽  
Biomedical Applications ◽  
Microprobe Analysis ◽  
Tissue Sample ◽  
Cellular Level ◽  
Tissue Samples ◽  
Asbestos Fibers

At present most medical microprobe analysis is conducted on insoluble particulates such as asbestos fibers in lung tissue. Cryotechniques are not necessary for this type of specimen. Insoluble particulates can be processed conventionally. Nevertheless, it is important to emphasize that conventional processing is unacceptable for specimens in which electrolyte distributions in tissues are sought. It is necessary to flash-freeze in order to preserve the integrity of electrolyte distributions at the subcellular and cellular level. Ideally, biopsies should be flash-frozen in the operating room rather than being frozen several minutes later in a histology laboratory. Electrolytes will move during such a long delay. While flammable cryogens such as propane obviously cannot be used in an operating room, liquid nitrogen-cooled slam-freezing devices or guns may be permitted, and are the best way to achieve an artifact-free, accurate tissue sample which truly reflects the in vivo state. Unfortunately, the importance of cryofixation is often not understood. Investigators bring tissue samples fixed in glutaraldehyde to a microprobe laboratory with a request for microprobe analysis for electrolytes.

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