Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish

RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of RAD51 loss. Zebrafish rad51 loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Comutation of p53 was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment of RAD51 as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.We thank the Sanger Institute Zebrafish Mutation Project for supplying the rad51sa23805 allele; Sebastian Gerety for supplying the tp53zdf1 line; Yvette Hooks for her help with histology; and the Sanger Institute FACS core facility and Charlotte Labalette for their experimental help. This work was supported by Cancer Research UK Grant C45041/A14953 (to A.C.); a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute; and a European Hematology Association–Jose Carreras Foundation Young Investigator Award and Isaac Newton Trust grant (to A.C.)

Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial-mesenchymal transition and poor overall survival.

BACKGROUND: Copy-number gain of the oncostatin-M receptor (OSMR) occurs frequently in cervical squamous cell carcinoma (SCC) and is associated with adverse clinical outcome. We previously showed that OSMR overexpression renders cervical SCC cells more sensitive to the major ligand oncostatin-M (OSM), which increases migration and invasion in vitro. We hypothesised that a major contribution to this phenotype would come from epithelial-mesenchymal transition (EMT). METHODS: We performed a comprehensive integrated study, involving in vitro cell line studies, in vivo animal models and numerous clinical samples from a variety of anatomical sites. RESULTS: In independent sets of cervical, head/neck and lung SCC tissues, OSMR expression levels correlated with multiple EMT-associated phenotypic markers and transcription factors. OSM treatment of OSMR overexpressing cervical SCC cells produced consistent EMT changes and increased tumour sphere formation in suspension culture. In a mouse model, OSMR overexpressing SCC cells treated with OSM showed significant increases in lung colonisation. The biological effects of exogenous OSM were mirrored by highly significant adverse overall survival in cervical SCCs with OSMR overexpression (N=251). CONCLUSIONS: OSM:OSMR interactions are able to induce EMT, increased cancer stem cell-like properties and enhanced lung colonisation in SCC cells. These changes are likely to contribute to the highly significant adverse outcome associated with OSMR overexpression in cervical SCCs.This work was supported by Cancer Research UK (Programme Grant A13080).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group

„Social Manufacturing and Logistics“ – Arbeit in der digitalisierten Produktion

Der Beitrag beruht auf Arbeiten des Forschungsprojektes „SoMaLI“ (Social Manufacturing and Logistics), das vom BMWi im Rahmen des Technologieprogramms „Autonomik für Industrie 4.0“ gefördert wird. Hierbei werden u. a. Experteninterviews in Interessenverbänden (V1-V3), Entwicklerbetrieben (E1-E3) und Anwenderunternehmen (A1-A4) durchgeführt. Das Projekt wird an der Technischen Universität Dortmund in Kooperation des Forschungsgebietes Industrie- und Arbeitsforschung (FIA) und des Lehrstuhls für Förder- und Lagerwesen (FLW) durchgeführt. Zur SoMaLI-Projektgruppe gehören Hartmut Hirsch-Kreinsen, Michael ten Hompel, Peter Ittermann, Johannes Dregger, Jonathan Niehaus, Thomas Kirks und Benedikt Mättig