463 research outputs found
Revisiting the Tenascins: Exploitable as Cancer Targets?
For their full manifestation, tumors require support from the surrounding tumor microenvironment (TME), which includes a specific extracellular matrix (ECM), vasculature, and a variety of non-malignant host cells. Together, these components form a tumor-permissive niche that significantly differs from physiological conditions. While the TME helps to promote tumor progression, its special composition also provides potential targets for anti-cancer therapy. Targeting tumor-specific ECM molecules and stromal cells or disrupting aberrant mesenchyme-cancer communications might normalize the TME and improve cancer treatment outcome. The tenascins are a family of large, multifunctional extracellular glycoproteins consisting of four members. Although each have been described to be expressed in the ECM surrounding cancer cells, tenascin-C and tenascin-W are currently the most promising candidates for exploitability and clinical use as they are highly expressed in various tumor stroma with relatively low abundance in healthy tissues. Here, we review what is known about expression of all four tenascin family members in tumors, followed by a more thorough discussion on tenascin-C and tenascin-W focusing on their oncogenic functions and their potential as diagnostic and/or targetable molecules for anti-cancer treatment purposes
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RSK Activation of Translation Factor eIF4B Drives Abnormal Increases of Laminin γ2 and MYC Protein during Neoplastic Progression to Squamous Cell Carcinoma
Overexpression of the basement membrane protein Laminin γ2 (Lamγ2) is a feature of many epidermal and oral dysplasias and all invasive squamous cell carcinomas (SCCs). This abnormality has potential value as an immunohistochemical biomarker of premalignancy but its mechanism has remained unknown. We recently reported that Lamγ2 overexpression in culture is the result of deregulated translation controls and depends on the MAPK-RSK signaling cascade. Here we identify eIF4B as the RSK downstream effector responsible for elevated Lamγ2 as well as MYC protein in neoplastic epithelial cells. Premalignant dysplastic keratinocytes, SCC cells, and keratinocytes expressing the E6 oncoprotein of human papillomavirus (HPV) type 16 displayed MAPK-RSK and mTOR-S6K1 activation and overexpressed Lamγ2 and MYC in culture. Immunohistochemical staining of oral dysplasias and SCCs for distinct, RSK- and S6K1-specific S6 phosphorylation events revealed that their respective upstream pathways become hyperactive at the same time during neoplastic progression. However, pharmacologic kinase inhibitor studies in culture revealed that Lamγ2 and MYC overexpression depends on MAPK-RSK activity, independent of PI3K-mTOR-S6K1. eIF4B knockdown reduced Lamγ2 and MYC protein expression, consistent with the known requirement for eIF4B to translate mRNAs with long, complex 5′ untranslated regions (5′-UTRs). Accordingly, expression of a luciferase reporter construct preceded by the Lamγ2 5′-UTR proved to be RSK-dependent and mTOR-independent. These results demonstrate that RSK activation of eIF4B is causally linked to elevated Lamγ2 and MYC protein levels during neoplastic progression to invasive SCC. These findings have potential clinical significance for identifying premalignant lesions and for developing targeted drugs to treat SCC
Rapid flipping of parametric phase states
Since the invention of the solid-state transistor, the overwhelming majority
of computers followed the von Neumann architecture that strictly separates
logic operations and memory. Today, there is a revived interest in alternative
computation models accompanied by the necessity to develop corresponding
hardware architectures. The Ising machine, for example, is a variant of the
celebrated Hopfield network based on the Ising model. It can be realized with
artifcial spins such as the `parametron' that arises in driven nonlinear
resonators. The parametron encodes binary information in the phase state of its
oscillation. It enables, in principle, logic operations without energy transfer
and the corresponding speed limitations. In this work, we experimentally
demonstrate flipping of parametron phase states on a timescale of an
oscillation period, much faster than the ringdown time \tau that is often
(erroneously) deemed a fundamental limit for resonator operations. Our work
establishes a new paradigm for resonator-based logic architectures.Comment: 6 pages, 3 figure
The Expression and Possible Functions of Tenascin-W During Development and Disease
Tenascins are a family of multifunctional glycoproteins found in the extracellular matrix of chordates. Two of the tenascins, tenascin-C and tenascin-W, form hexabrachions. In this review, we describe the discovery and domain architecture of tenascin-W, its evolution and patterns of expression during embryogenesis and in tumors, and its effects on cells in culture. In avian and mammalian embryos tenascin-W is primarily expressed at sites of osteogenesis, and in the adult tenascin-W is abundant in certain stem cell niches. In primary cultures of osteoblasts tenascin-W promotes cell migration, the formation of mineralized foci and increases alkaline phosphatase activity. Tenascin-W is also prominent in many solid tumors, yet it is missing from the extracellular matrix of most adult tissues. This makes it a potential candidate for use as a marker of tumor stroma and a target for anti-cancer therapies
Spatially resolved surface dissipation over metal and dielectric substrates
We report spatially resolved measurements of static and fluctuating electric
fields over conductive (Au) and non-conductive (SiO2) surfaces. Using an
ultrasensitive `nanoladder' cantilever probe to scan over these surfaces at
distances of a few tens of nanometers, we record changes in the probe resonance
frequency and damping that we associate with static and fluctuating fields,
respectively. We find that the two quantities are spatially correlated and of
similar magnitude for the two materials. We quantitatively describe the
observed effects on the basis of trapped surface charges and dielectric
fluctuations in an adsorbate layer. Our results provide direct, spatial
evidence for surface dissipation in adsorbates that affects nanomechanical
sensors, trapped ions, superconducting resonators, and color centers in
diamond
Discovery and characterization of heterogeneous and multipotent fibroblast populations isolated from excised cleft lip tissue.
BACKGROUND
Regularly discarded lip tissue obtained from corrective surgeries to close the cleft lip represents an easily accessible and rich source for the isolation of primary fibroblasts. Primary fibroblasts have been described to show compelling similarities to mesenchymal stem cells (MSCs). Hence, cleft lip and palate (CLP) lip-derived fibroblasts could be thought as an intriguing cell source for personalized regenerative therapies in CLP-affected patients.
METHODS
Initially, we thoroughly characterized the fibroblastic nature of the lip-derived mesenchymal outgrowths by molecular and functional assays. Next, we compared their phenotype and genotype to that of bone marrow-mesenchymal stem cells (BM-MSCs) and of human lung-derived fibroblasts WI38, by assessing their morphology, surface marker expression, trilineage differentiation potential, colony-forming (CFU) capacity, and immunomodulation property. Finally, to better decipher the heterogeneity of our CLP cultures, we performed a single cell clonal analysis and tested expanded clones for surface marker expression, as well as osteogenic and CFU potential.
RESULTS
We identified intriguingly similar phenotypic and genotypic properties between CLP lip fibroblasts and BM-MSCs, which makes them distinct from WI38. Furthermore, our own data in combination with the complex anatomy of the lip tissue indicated heterogeneity in our CLP cultures. Using a clonal analysis, we discovered single cell-derived clones with increased levels of the MSC markers CD106 and CD146 and clones with variabilities in their commitment to differentiate into bone-forming cells and in their potential to form single cell-derived colonies. However, we were not able to gain clones possessing superior MSC-like capacities when compared to the heterogeneous parental CLP population. Additionally, all clones could still generate contractile forces and retained robust levels of the fibroblast specific marker FSP1, which was not detectable in BM-MSCs.
CONCLUSIONS
Our results suggest that we isolate heterogeneous populations of fibroblasts from discarded CLP lip tissue, which show a prominently multipotent character in their entirety avoiding the need for elaborate subpopulation selections in vitro. These findings suggest that CLP lip fibroblasts might be a novel potential cell source for personalized regenerative medicine of clinical benefit for CLP patients
Lack of IRF6 Disrupts Human Epithelial Homeostasis by Altering Colony Morphology, Migration Pattern, and Differentiation Potential of Keratinocytes.
Variants within the gene encoding for the transcription factor Interferon Regulatory Factor 6 (IRF6) are associated with syndromic and non-syndromic Cleft Lip/Palate (CLP) cases. IRF6 plays a vital role in the regulation of the proliferation/differentiation balance in keratinocytes and is involved in wound healing and migration. Since a fraction of CLP patients undergoing corrective cleft surgery experience wound healing complications, IRF6 represents an interesting candidate gene linking the two processes. However, Irf6 function has been mainly studied in mice and knowledge on IRF6 in human cells remains sparse. Here, we aimed to elucidate the role of IRF6 in human postnatal skin- and oral mucosa-derived keratinocytes. To do so, we applied CRISPR/Cas9 to ablate IRF6 in two TERT-immortalized keratinocyte cultures, which we used as model cell lines. We show that IRF6 controls the appearance of single cells and colonies, with the latter being less cohesive in its absence. Consequently, IRF6 knockout keratinocytes often moved as single cells instead of a collective epithelial sheet migration but maintained their epithelial character. Lack of IRF6 triggered severe keratinocyte differentiation defects, which were already apparent in the stratum spinosum and extended to the stratum corneum in 3D organotypic skin cultures, while it did not alter their growth rate. Finally, proteomics revealed that most of the differentially expressed proteins in the absence of IRF6 could be associated with differentiation, cell-cell adhesion as well as immune response. Our data expand the knowledge on IRF6 in human postnatal keratinocytes, which will help to better understand IRF6-related pathologies
High-speed domain wall racetracks in a magnetic insulator
Recent reports of current-induced switching of ferrimagnetic oxides coupled
to a heavy metal layer have opened realistic prospects for implementing
magnetic insulators into electrically addressable spintronic devices. However,
key aspects such as the configuration and dynamics of magnetic domain walls
driven by electrical currents in insulating oxides remain unexplored. Here, we
investigate the internal structure of the domain walls in Tm3Fe5O12 (TmIG) and
TmIG/Pt bilayers and demonstrate their efficient manipulation by spin-orbit
torques with velocities of up to 400 m s and minimal current threshold
for domain wall flow of 5 x 10 A cm. Domain wall racetracks
embedded in TmIG are defined by the deposition of Pt current lines, which allow
us to control the domain propagation and magnetization switching in selected
regions of an extended magnetic layer. Scanning nitrogen-vacancy magnetometry
reveals that the domain walls of thin TmIG films are N\'eel walls with
left-handed chirality, with the domain wall magnetization rotating towards an
intermediate N\'eel-Bloch configuration upon deposition of Pt. These results
indicate the presence of a sizable interfacial Dzyaloshinskii-Moriya
interaction in TmIG, which leads to novel possibilities to control the
formation of chiral spin textures in magnetic insulators. Ultimately, domain
wall racetracks provide an efficient scheme to pattern the magnetic landscape
of TmIG in a fast and reversible wa
Increasing metabolic potential: C-fixation
Due to a growing world population, crop yields must increase to meet rising demand. Crop plants also require adaptation to optimise performance in the changing environments caused by climate change. Improving photosynthetic carbon fixation is a promising, albeit technically challenging, strategy whose potential has only just begun to be considered in breeding programs. Rubisco, a fundamental enzyme of carbon fixation, is extremely inefficient and many strategies to improve photosynthesis focus on overcoming the limitations of this enzyme, either by improving Rubisco activity and regulation or by improving the supply of substrates. Although progress is being made, the need to tailor solutions for each crop and their respective environments has been highlighted. Even so, continuing research will be required to achieve these objectives and to grow crops more sustainably in the future
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