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"Morrison, Helen"
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Pathomechanisms in schwannoma development and progression
Schwannomas are tumors of the peripheral nervous system, consisting of different cell types. These include tumorigenic Schwann cells, axons, macrophages, T cells, fibroblasts, blood vessels, and an extracellular matrix. All cell types involved constitute an intricate “tumor microenvironment” and play relevant roles in the development and progression of schwannomas. Although Nf2 tumor suppressor gene-deficient Schwann cells are the primary tumorigenic element and principle focus of current research efforts, evidence is accumulating regarding the contributory roles of other cell types in schwannoma pathology. In this review, we aim to provide an overview of intra- and intercellular mechanisms contributing to schwannoma formation.“Genes load the gun, environment pulls the trigger.”-George A. Bray
Journal Article
The yellow house
A little girl's fascination with the yellow house she passes each day leads her into its garden which is full of fantastic surprises.
Book
Inflammaging impairs peripheral nerve maintenance and regeneration
The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.
Journal Article
Superyachts : luxury, tranquility and ecocide
A superyacht is a boat that exceeds 30 metres in length, with some surpassing even 100 metres - more than a football field. At the beginning of the 21st century, there were about 2,000 of these vessels in the world; two decades and a financial crisis later, there are three times as many. Gregory Salle argues that these are not whimsical fads: on the contrary, luxury yachting highlights the social exclusivity of the wealthiest and the environmental waste they emit. Rather than being simply the plaything of billionaires with extravagant lifestyles, the superyacht offers a disconcerting reflection of the world as it is.
Book
The importance of nerve microenvironment for schwannoma development
Schwannomas are predominantly benign nerve sheath neoplasms caused by
Nf2
gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of
Nf2
gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with injury signals contribute to a persistent regenerative Schwann cell response promoting schwannoma development. Specifically in genetically engineered mice following crush injuries on sciatic nerves, we found macroscopic nerve swellings in mice with homozygous
nf2
gene deletion in Schwann cells and in animals with heterozygous
nf2
knockout in both Schwann cells and axons. However, patient-mimicking schwannomas could only be provoked in animals with combined heterozygous
nf2
knockout in Schwann cells and axons. We identified a severe re-myelination defect and sustained macrophage presence in the tumor tissue as major abnormalities. Strikingly, treatment of tumor-developing mice after nerve crush injury with medium-dose aspirin significantly decreased schwannoma progression in this disease model. Our results suggest a multifactorial concept for schwannoma formation—emphasizing axonal factors and mechanical nerve irritation as predilection site for schwannoma development. Furthermore, we provide evidence supporting the potential efficacy of anti-inflammatory drugs in the treatment of schwannomas.
Journal Article
Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase
Tumour-causing cascade
The phosphatase that activates the Merlin tumour suppressor (also known as neurofibromatosis 2) has been identified. It's a myosin phosphatase that is inhibited by the endogenous inhibitor CPI-17, which is often upregulated in human tumours and may contribute to the development of cancer by inactivating Merlin. Taken together, these findings point to a novel cascade of tumour suppressors whose action can be abolished in at least two ways, by mutation (NF2) or upregulation of the putative novel oncogene, CPI-17.
A phosphatase that activates the tumour suppressor protein merlin is identified. An endogenous inhibitor of this phosphatase is often upregulated in human tumours and may contribute to the development of cancer by inactivating merlin.
The tumour suppressor protein merlin (encoded by the neurofibromatosis type 2 gene
NF2
) is an important regulator of proliferation in many cell and tissue types
1
,
2
,
3
,
4
. Merlin is activated by dephosphorylation at serine 518 (S518), which occurs on serum withdrawal or on cell–cell or cell–matrix contact
5
,
6
. However, the relevant phosphatase that activates merlin's tumour suppressor function is unknown. Here we identify this enzyme as the myosin phosphatase (MYPT-1–PP1δ). The cellular MYPT-1–PP1δ-specific inhibitor CPI-17 causes a loss of merlin function characterized by merlin phosphorylation, Ras activation and transformation. Constitutively active merlin (S518A) reverses CPI-17-induced transformation, showing that merlin is the decisive substrate of MYPT-1–PP1δ in tumour suppression. In addition we show that CPI-17 levels are raised in several human tumour cell lines and that the downregulation of CPI-17 induces merlin dephosphorylation, inhibits Ras activation and abolishes the transformed phenotype. MYPT-1–PP1δ and its substrate merlin are part of a previously undescribed tumour suppressor cascade that can be hindered in two ways, by mutation of the
NF2
gene and by upregulation of the oncoprotein CPI-17.
Journal Article
Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane
Receptor tyrosine kinases (RTKs) participate in a multitude of signaling pathways, some of them via the small G-protein Ras. An important component in the activation of Ras is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras.
We can now demonstrate that the activation of Ras requires, in addition, the essential participation of ezrin, radixin and/or moesin (ERM), a family of actin-binding proteins, and of actin. Disrupting either the interaction of the ERM proteins with co-receptors, down-regulation of ERM proteins by siRNA, expression of dominant-negative mutants of the ERM proteins or disruption of F-actin, abolishes growth factor-induced Ras activation. Ezrin/actin catalyzes the formation of a multiprotein complex consisting of RTK, co-receptor, Grb2, SOS and Ras. We also identify binding sites for both Ras and SOS on ezrin; mutations of these binding sites destroy the interactions and inhibit Ras activation. Finally, we show that the formation of the ezrin-dependent complex is necessary to enhance the catalytic activity of SOS and thereby Ras activation.
Taking these findings together, we propose that the ERM proteins are novel scaffolds at the level of SOS activity control, which is relevant for both normal Ras function and dysfunction known to occur in several human cancers.
Journal Article
Neurofibromatosis type 2 tumor suppressor protein is expressed in oligodendrocytes and regulates cell proliferation and process formation
The neurofibromatosis type 2 (NF2) tumor suppressor protein Merlin functions as a negative regulator of cell growth and actin dynamics in different cell types amongst which Schwann cells have been extensively studied. In contrast, the presence and the role of Merlin in oligodendrocytes, the myelin forming cells within the CNS, have not been elucidated. In this work, we demonstrate that Merlin immunoreactivity was broadly distributed in the white matter throughout the central nervous system. Following Merlin expression during development in the cerebellum, Merlin could be detected in the cerebellar white matter tract at early postnatal stages as shown by its co-localization with Olig2-positive cells as well as in adult brain sections where it was aligned with myelin basic protein containing fibers. This suggests that Merlin is expressed in immature and mature oligodendrocytes. Expression levels of Merlin were low in oligodendrocytes as compared to astrocytes and neurons throughout development. Expression of Merlin in oligodendroglia was further supported by its identification in either immortalized cell lines of oligodendroglial origin or in primary oligodendrocyte cultures. In these cultures, the two main splice variants of Nf2 could be detected. Merlin was localized in clusters within the nuclei and in the cytoplasm. Overexpressing Merlin in oligodendrocyte cell lines strengthened reduced impedance in XCELLigence measurements and Ki67 stainings in cultures over time. In addition, the initiation and elongation of cellular projections were reduced by Merlin overexpression. Consistently, cell migration was retarded in scratch assays done on Nf2-transfected oligodendrocyte cell lines. These data suggest that Merlin actively modulates process outgrowth and migration in oligodendrocytes.
Journal Article
Impact of inflammatory preconditioning on murine microglial proteome response induced by focal ischemic brain injury
Preconditioning with lipopolysaccharide (LPS) induces neuroprotection against subsequent cerebral ischemic injury, mainly involving innate immune pathways. Microglia are resident immune cells of the central nervous system (CNS) that respond early to danger signals through memory-like differential reprogramming. However, the cell-specific molecular mechanisms underlying preconditioning are not fully understood. To elucidate the distinct molecular mechanisms of preconditioning on microglia, we compared these cell-specific proteomic profiles in response to LPS preconditioning and without preconditioning and subsequent transient focal brain ischemia and reperfusion, – using an established mouse model of transient focal brain ischemia and reperfusion. A proteomic workflow, based on isolated microglia obtained from mouse brains by cell sorting and coupled to mass spectrometry for identification and quantification, was applied. Our data confirm that LPS preconditioning induces marked neuroprotection, as indicated by a significant reduction in brain infarct volume. The established brain cell separation method was suitable for obtaining an enriched microglial cell fraction for valid proteomic analysis. The results show a significant impact of LPS preconditioning on microglial proteome patterns by type I interferons, presumably driven by the interferon cluster regulator proteins signal transducer and activator of transcription1/2 (STAT1/2).
Journal Article