Global Proteome and Phospho-proteome Analysis of Merlin-deficient Meningioma and Schwannoma Identifies PDLIM2 as a Novel Therapeutic Target

Loss or mutation of the tumour suppressor Merlin predisposes individuals to develop multiple nervous system tumours, including schwannomas and meningiomas, sporadically or as part of the autosomal dominant inherited condition Neurofibromatosis 2 (NF2). These tumours display largely low grade features but their presence can lead to significant morbidity. Surgery and radiotherapy remain the only treatment options despite years of research, therefore an effective therapeutic is required. Unbiased omics studies have become pivotal in the identification of differentially expressed genes and proteins that may act as drug targets or biomarkers. Here we analysed the proteome and phospho-proteome of these genetically defined tumours using primary human tumour cells to identify upregulated/activated proteins and/or pathways. We identified over 2000 proteins in comparative experiments between Merlin-deficient schwannoma and meningioma compared to human Schwann and meningeal cells respectively. Using functional enrichment analysis we highlighted several dysregulated pathways and Gene Ontology terms. We identified several proteins and phospho-proteins that are more highly expressed in tumours compared to controls. Among proteins jointly dysregulated in both tumours we focused in particular on PDZ and LIM domain protein 2 (PDLIM2) and validated its overexpression in several tumour samples, while not detecting it in normal cells. We showed that shRNA mediated knockdown of PDLIM2 in both primary meningioma and schwannoma leads to significant reductions in cellular proliferation. To our knowledge, this is the first comprehensive assessment of the NF2-related meningioma and schwannoma proteome and phospho-proteome. Taken together, our data highlight several commonly deregulated factors, and indicate that PDLIM2 may represent a novel, common target for meningioma and schwannoma

Fire & Flower in the Cochlea oder Wie die Haarsinneszellen im Innenohr in Abhängigkeit von Thyroidhormon erblühen

Zusammenfassung In der kritischen Entwicklungsperiode des Innenohres, die mit dem Beginn der Hörfunktion endet - im Menschen ungefähr zwischen der zehnten und zwanzigsten embryonalen Woche, in Nagetieren wie Ratte und Maus zwischen Geburt und postnatalem Tag 12 (P12) - erfährt das Hörorgan einen terminalen Reifungsprozess, der insbesondere die synchrone morphogenetische, neuronale und zelluläre Differenzierung des Cortischen Organs umfasst. Wie wichtig gerade dieses Zeitfenster für die Entwicklung unserer Hörfähigkeit ist, zeigt sich darin, dass sich genetisch bedingte und erworbene Innenohrdefekte bevorzugt in dieser kritischen Entwicklungsperiode manifestieren. Während seit Dekaden bekannt ist, dass Schilddrüsenhormon-Mangel (Hypothyreose) Taubheit, mentale Retardation und Minderwuchs hervorrufen kann, beginnt man die molekularen Ursachen der Schwerhörigkeit bei Hypothyreose gerade erst im Detail zu verstehen. Ein erster überraschender Befund in unserem Labor war, dass das Thyroidhormon (TH) für die Entwicklung einer normalen Hörfunktion ausschließlich in der kritischen Entwicklungsperiode vor Hörfunktionsbeginn benötigt wird. Innerhalb dieser Zeit beeinflusst TH Stufe um Stufe von der Peripherie in Richtung Kortex terminale Differenzierungsprozesse über transkriptionelle Stimulation und Suppression von Genen. Die Identifizierung der in dieser Zeit durch TH regulierten Gene, ebenso wie das Studium ihrer Regulatoren, zeigt uns neue Ursachen für genetisch bedingte und erworbene Taubheit auf.</jats:p

Felsenbeinhistopathologie nach tiefer Cochlea Implantation

Sudhoff H, Ebmeyer J, Bernal-Sprekelsen M, et al. Felsenbeinhistopathologie nach tiefer Cochlea Implantation. Laryngo-Rhino-Otologie. 2010;89(02):95-97

Evaluation of vascular endothelial growth factor addition in vitro on mouse inner ear progenitor cell cultures

We analyzed progenitor cell cultures of inner ear tissue from newborn mice, and found proliferating cells, morphologically differentiating cells and subpopulations of cells expressing either neuronal or glial markers. In addition, we observed the expression of fetal liver kinase-1, a receptor for the vascular endothelial growth factor in a subpopulation of the cultured cells. Consistent with the expression of fetal liver kinase-1, addition of vascular endothelial growth factor at a dose of 10 ng/ml increased the expansion rate of inner ear-derived progenitor cells. Together with other published data, these results suggest that the vascular endothelial growth factor might be involved in inducing or supporting cochlear repair processes

Supporting Equity and Inclusion of Deaf and Hard-of-Hearing Individuals in Professional Organizations

Disability is an important and often overlooked component of diversity. Individuals with disabilities bring a rare perspective to science, technology, engineering, mathematics, and medicine (STEMM) because of their unique experiences approaching complex issues related to health and disability, navigating the healthcare system, creatively solving problems unfamiliar to many individuals without disabilities, managing time and resources that are limited by physical or mental constraints, and advocating for themselves and others in the disabled community. Yet, individuals with disabilities are underrepresented in STEMM. Professional organizations can address this underrepresentation by recruiting individuals with disabilities for leadership opportunities, easing financial burdens, providing equal access, fostering peer-mentor groups, and establishing a culture of equity and inclusion spanning all facets of diversity. We are a group of deaf and hard-of-hearing (D/HH) engineers, scientists, and clinicians, most of whom are active in clinical practice and/or auditory research. We have worked within our professional societies to improve access and inclusion for D/HH individuals and others with disabilities. We describe how different models of disability inform our understanding of disability as a form of diversity. We address heterogeneity within disabled communities, including intersectionality between disability and other forms of diversity. We highlight how the Association for Research in Otolaryngology has supported our efforts to reduce ableism and promote access and inclusion for D/HH individuals. We also discuss future directions and challenges. The tools and approaches discussed here can be applied by other professional organizations to include individuals with all forms of diversity in STEMM.National Institute of Neurological Disorders and Stroke http://dx.doi.org/10.13039/100000065National Institute of General Medical Sciences http://dx.doi.org/10.13039/10000005

Nilotinib alone or in combination with selumetinib is a drug candidate for neurofibromatosis type 2

Loss of the tumor suppressor merlin is a cause of frequent tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis type 2 (NF2). Because there is medical need for drug therapies for these tumors, our aim is to find therapeutic targets. We have studied the pathobiology of schwannomas, because they are the most common merlin-deficient tumors and are a model for all merlin-deficient tumors. With use of a human schwannoma in vitro model, we previously described strong overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) leading to strong, long-lasting activation of extracellular-signal-regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we successfully inhibited using the PDGFR/Raf inhibitor sorafenib. However, the benign character of schwannomas may require long-term treatment; thus, drug tolerability is an issue. With the use of Western blotting, proliferation assays, viability assays, and a primary human schwannoma cell in vitro model, we tested the PDGFR/c-KIT inhibitors imatinib (Glivec; Novartis) and nilotinib (Tasigna; Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR-β and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. In addition, nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displayed stronger efficiency toward tumor growth inhibition, compared with nilotinib alone. We suggest that therapy with nilotinib or combinational therapy that  simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors