Roberto Ferrarese

University of Freiburg

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Maria Stella Carro

University of Freiburg

Eva Kling

University of Freiburg

Anie P. Masilamani

University of Freiburg

Astrid Weyerbrock

University of Freiburg

Dieter Henrik Heiland

University of Freiburg

Marco Prinz

University of Freiburg

Fangping Dai

Second People's Hospital of NanTong

Annalisa Grimaldi

University of Insubria

Sven Nelander

Uppsala University

Gianluca Tettamanti

University of Insubria

Cooperative Institutions

University of Freiburg

University Medical Center Freiburg

University of Alabama at Birmingham

University of Insubria

Universidad de Navarra

Universidade de São Paulo

Northwestern University

The University of Texas MD Anderson Cancer Center

Navarre Institute of Health Research

Neurological Surgery

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NFKBIADeletion in Glioblastomas

New England Journal of Medicine (2010)

Markus Bredel Denise Scholtens Ajay K. Yadav Angel A. Alvarez Jaclyn J. Renfrow

Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR.We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons.NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease.Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.

10.1056/nejmoa1006312

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A supracellular system of actin-lined canals controls biogenesis and release of virulence factors in parasitoid venom glands

Journal of Experimental Biology (2009)

Roberto Ferrarese Jorge Morales Daniel Fimiarz Bruce A. Webb Shubha Govind

Parasitoid wasps produce virulence factors that bear significant resemblance to viruses and have the ability to block host defense responses. The function of these virulence factors, produced predominantly in wasp venom glands, and the ways in which they interfere with host development and physiology remain mysterious. Here, we report the discovery of a specialized system of canals in venom glands of five parasitoid wasps that differ in their infection strategies. This supracellular canal system is made up of individual secretory units, one per secretory cell. Individual units merge into the canal lumen. The membrane surface of the proximal end of each canal within the secretory cell assumes brush border morphology, lined with bundles of F-actin. Systemic administration of cytochalasin D compromises the integrity of the secretory unit. We show a dynamic and continuous association of p40, a protein of virus-like particles from a Drosophila parasitoid, L. heterotoma, with the canal and venom gland lumen. Similar structures in three Leptopilina species and Ganaspis xanthopoda, parasitoids of Drosophila spp., and Campoletis sonorenesis, a parasitoid of Heliothis virescens, suggest that this novel supracellular canal system is likely to be a common trait of parasitoid venom glands that is essential for efficient biogenesis and delivery of virulence factors.

Heliothis virescens

10.1242/jeb.025718

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Role for Sumoylation in Systemic Inflammation and Immune Homeostasis in Drosophila Larvae

PLoS Pathogens (2010)

Indira Paddibhatla Mark J. Lee Marta E. Kalamarz Roberto Ferrarese Shubha Govind

To counter systemic risk of infection by parasitic wasps, Drosophila larvae activate humoral immunity in the fat body and mount a robust cellular response resulting in encapsulation of the wasp egg. Innate immune reactions are tightly regulated and are resolved within hours. To understand the mechanisms underlying activation and resolution of the egg encapsulation response and examine if failure of the latter develops into systemic inflammatory disease, we correlated parasitic wasp-induced changes in the Drosophila larva with systemic chronic conditions in sumoylation-deficient mutants. We have previously reported that loss of either Cactus, the Drosophila (IκB) protein or Ubc9, the SUMO-conjugating enzyme, leads to constitutive activation of the humoral and cellular pathways, hematopoietic overproliferation and tumorogenesis. Here we report that parasite infection simultaneously activates NF-κB-dependent transcription of Spätzle processing enzyme (SPE) and cactus. Endogenous Spätzle protein (the Toll ligand) is expressed in immune cells and excessive SPE or Spätzle is pro-inflammatory. Consistent with this function, loss of Spz suppresses Ubc9− defects. In contrast to the pro-inflammatory roles of SPE and Spätzle, Cactus and Ubc9 exert an anti-inflammatory effect. We show that Ubc9 maintains steady state levels of Cactus protein. In a series of immuno-genetic experiments, we demonstrate the existence of a robust bidirectional interaction between blood cells and the fat body and propose that wasp infection activates Toll signaling in both compartments via extracellular activation of Spätzle. Within each organ, the IκB/Ubc9-dependent inhibitory feedback resolves immune signaling and restores homeostasis. The loss of this feedback leads to chronic inflammation. Our studies not only provide an integrated framework for understanding the molecular basis of the evolutionary arms race between insect hosts and their parasites, but also offer insights into developing novel strategies for medical and agricultural pest control.

Wiskott–Aldrich syndrome protein

10.1371/journal.ppat.1001234

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Structure and function of the extraembryonic membrane persisting around the larvae of the parasitoid Toxoneuron nigriceps

Journal of Insect Physiology (2006)

Annalisa Grimaldi Silvia Caccia Terenzio Congiu Roberto Ferrarese Gianluca Tettamanti

10.1016/j.jinsphys.2006.05.011

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Distinct Pattern of Membrane Formation With Spinal Cerebrospinal Fluid Leaks in Spontaneous Intracranial Hypotension

Operative Neurosurgery (2023)

Levin Häni Christian Fung Amir El Rahal Florian Volz Luisa Mona Kraus

BACKGROUND AND OBJECTIVES: To systematically describe pertinent, intraoperative anatomic findings encountered when approaching spinal cerebrospinal fluid (CSF) leaks and CSF-venous fistulas in spontaneous intracranial hypotension (SIH). METHODS: In a retrospective study, we included surgically treated patients suffering from SIH at our institution from April 2018 to March 2022. Anatomic, intraoperative data were extracted from operative notes and supplemented with data from surgical videos and images. Prominent anatomic features were compared among different types of CSF leaks. RESULTS: The study cohort consists of 120 patients with a mean age of 45.2 years. We found four distinct patterns of spinal membranes specifically associated with different types of CSF leaks: (i) thick, dorsal membranes, which were hypervascular and may mimic the dura (pseudodura); (ii) thin, lateral membranes encapsulating a ventral epidural CSF compartment (confining the spinal longitudinal extradural CSF collection); (iii) ventral membranes constituting a transdural funnel–like CSF channel; and (iv) lateral membranes forming spinal cysts/meningeal diverticulae associated with lateral CSF leaks. The latter three types resemble a layer of arachnoid herniated through the dural defect. CONCLUSION: We describe four distinct spinal (neo-)membranes in association with spinal CSF leaks. Formation of these membranes, or emergence by herniation of arachnoid through a dural defect, constitutes a specific pathoanatomic feature of patients with SIH and CSF leaks. Recognition of these membranes is of paramount importance for diagnosis and treatment of patients with spinal CSF leaks.

Cerebrospinal fluid leak

10.1227/ons.0000000000000914

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Citations (10)

[Hyperandrogenic variations in pregnancy].

PubMed (1968)

D Colavita D Giacopino Roberto Ferrarese

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Neural networks help zebrafish to step up as a model for efficient drug screening in glioblastoma

Neuro-Oncology (2022)

Roberto Ferrarese Maria Stella Carro

In spite of the intensive search for a cure, glioblastoma (GBM) is still a deadly tumor with no effective treatment available. Therefore, there is an urgent need for new therapies. Most of the current research is based on orthotopic patient-derived xenograft (PDX) mouse models. Although certainly valuable for the characterization of tumor-associated mechanisms involving altered gene functions, these models are less suitable for large-scale drug screening and high-throughput studies. In fact, the maintenance of the mice from the injection of GBM cells to the animal sacrifice at the experimental endpoint, is quite expensive and time-consuming. Moreover, in large-scale drug screenings, there are also ethical concerns associated with the use of large numbers of higher vertebrates. In an attempt to overcome these hindrances, the zebrafish model has gained attention in the past years as an approachable model for cancer studies. This rapidly growing, low maintenance fish represents a worth-investigating opportunity to assess the efficacy of novel therapeutic drugs in large-scale, high-throughput screenings. Zebrafish has been widely used in developmental studies, while the applicability to the characterization of cancer-associated mechanisms has been less extensively investigated. Recent studies have shown that cancer traits described in mammals can be efficiently reproduced in zebrafish.1 Features of the zebrafish brain such as its gross anatomical organization, its cell populations, and its regulatory signaling pathways, are conserved and shared by all vertebrates. Additionally, the lack of a functional adaptive system in early-stage development favors a fast and efficient tumor engraftment. Zebrafish small size and unique transparent feature allow visualizing fluorescent proteins under the skin by direct live imaging of the fishes; light-sheet microscopy can also be applied for the detailed visualization of cell migration processes in live animals. Taken together, these features have made zebrafish a promising xenograft model for GBM studies, so far prevalently focused on proliferation and on migratory/invasive properties of GBM cells.2–5

10.1093/neuonc/noac045

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BTC1.05 Role and significance of ZBTB18-CTBP2 interaction in Glioblastoma

Neuro-Oncology (2018)

Anie P. Masilamani Roberto Ferrarese Geoffroy Andrieux Eva Kling Melanie Börries

The Zing Finger And BTB Domain Containing 18 (ZBTB18; formerly ZNF238) is a transcriptional repressor with a crucial role in brain development and neuronal differentiation. We recently showed that ZBTB18 represses poor prognosis-associated genes and that it is primarily silenced in mesenchymal GBMs through promoter methylation. To further elucidate the mechanism of ZBTB18 function, we performed Mass Spectrometry (MS) analysis of ZBTB18 co-precipitated proteins in SNB19 cells upon ZBTB18 overexpression. Our data revealed that the corepressors CTBP1 and CTBP2 could be potential ZBTB18 interactors. CTBPs are co-repressors which are implicated in human cancer by promoting several pro-oncogenic activities including EMT, cell survival, migration and invasion. We validated the interactions between ZBTB18 and CTBP2 by co-immunoprecipitation; interestingly, ZBTB18 contains a putative CTBP2 interaction motif (VLDLS) further supporting its role as new CTBP2 interactor. Gene expression analysis followed by gene set enrichment showed that both ZBTB18 overexpression and CTBP2 silencing affect the expression of EMT-signatures, suggesting that the two proteins play an opposite role. As such, ZBTB18 binding to CTBP2 could interfere with CTBP2 function. SILAC-based quantitative mass spectrometry analysis suggests that upon ZBTB18 overexpression, CTBP2 is sequestered by CTBP2 causing the disruption of the CTBP1/2 repressive complex and consequent deregulated gene expression. Overall our data suggest a new mechanism of EMT suppression by ZBTB18 through sequestration of CTBP2 and disruption of the CTBP1/CTBP2 repressive complex. A deeper examination of the proposed mechanism of ZBTB18 function could be used to reverse the mesenchymal phenotype of GBM.

Immunoprecipitation

Corepressor

10.1093/neuonc/noy139.004

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Programmed cell death and stem cell differentiation are responsible for midgut replacement in Heliothis virescens during prepupal instar

Cell and Tissue Research (2007)

Gianluca Tettamanti Annalisa Grimaldi Morena Casartelli Elena Ambrosetti Benedetta Ponti

Heliothis virescens

10.1007/s00441-007-0449-8

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Characterization of the IκB-like gene family in polydnaviruses associated with wasps belonging to different Braconid subfamilies

Journal of General Virology (2006)

Patrizia Falabella Paola Varricchio Bertille Provost Eric Espagne Roberto Ferrarese

Polydnaviruses (PDVs) are obligate symbionts of hymenopteran parasitoids of lepidopteran larvae that induce host immunosuppression and physiological redirection. PDVs include bracoviruses (BVs) and ichnoviruses (IVs), which are associated with braconid and ichneumonid wasps, respectively. In this study, the gene family encoding I κ B-like proteins in the BVs associated with Cotesia congregata (CcBV) and Toxoneuron nigriceps (TnBV) was analysed. PDV-encoded I κ B-like proteins (ANK) are similar to insect and mammalian I κ B, an inhibitor of the transcription factor nuclear factor κ B (NF- κ B), but display shorter ankyrin domains and lack the regulatory domains for signal-mediated degradation and turnover. Phylogenetic analysis of ANK proteins indicates that those of IVs and BVs are closely related, even though these two taxa are believed to lack a common ancestor. Starting from a few hours after parasitization, the transcripts of BV ank genes were detected, at different levels, in several host tissues. The structure of the predicted proteins suggests that they may stably bind NF- κ B/Rel transcription factors of the tumour necrosis factor (TNF)/Toll immune pathway. Accordingly, after bacterial challenge of Heliothis virescens host larvae parasitized by T. nigriceps , NF- κ B immunoreactive material failed to enter the nucleus of host haemocytes and fat body cells. Moreover, transfection experiments in human HeLa cells demonstrated that a TnBV ank1 gene product reduced the efficiency of the TNF- α -induced expression of a reporter gene under NF- κ B transcriptional control. Altogether, these results suggest strongly that TnBV ANK proteins cause retention of NF- κ B/Rel factors in the cytoplasm and may thus contribute to suppression of the immune response in parasitized host larvae.

Ankyrin repeat

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10.1099/vir.0.82306-0

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Citations (63)