Highlights

Exosomes from irradiated head and neck tumors promote the migration of tumor cells

Exosomes from irradiated BHY cells enhance the migratory phenotype. Exemplary wound healing of BHY-GFP cells after 40 hours (scale bar: 500 µm). Cells were either preincubated with exosomes from non-irradiated (EXO 0 Gy) or 6 Gy (EXO 6 Gy) irradiated BHY cells.

For treatment head and neck tumors are often irradiated. Frequently, however, radiation resistance, local tumor recurrence and metastases impair the therapeutic success. Recent research by the scientists of the Institute of Radiation Biology (Institut für Strahlenbiologie – ISB) suggests that exosome-mediated cell-to-cell communication plays an important role in these processes. Corresponding study results were recently published in the journal Scientific Reports.

Dr. Simone Moertl’s team at the Institute of Radiation Biology investigated the influence of exosomes on the radiation response of head and neck tumor cells. Exosomes are nanosized, endosomally secreted vesicles. Surrounded by a double-lipid membrane, they transport proteins and nucleic acids to recipient cells and by doing so assume an important task in cellular communication. Initially, our scientists treated recipient cells with exosomes from irradiated cells. These showed a significantly higher migration than recipient cells after treatment with unexposed exosomes. "We attribute this to exosome-mediated activation of signaling cascades in the tumor recipient cells," says Dr Moertl. "Exosomes of irradiated cells activate the pro-survival and pro-migratory AKT signaling pathway. From a clinical perspective, this could also be a possible explanation for tumor growth and metastasis during radiotherapy." In cooperation with colleagues of the Core Facility Proteomics, our researchers where then able to identify 75 radiation-regulated exosomal proteins that induce increased AKT signaling.

These new findings in extracellular communication in tumor patients may support the development of novel radiation sensitization therapies. In future projects, the potential of exosomes as a marker to predict the response of tumors will be analyzed. This may be the first step to develop exosomes that allow an efficient transmission of drugs for the radiation sensitization of tumors.

 more information:

Mutschelknaus, L. et al (2017): Radiation alters the cargo of exosomes released from squamous head and neck cancer cells to promote migration of recipient cells. Scientific Reports. DOI: 10.1038/s41598-017-12403-6

Person to contact for further enquiries: PD Dr. Simone Moertl, ISB, Tel. -3143 E-Mail ()

A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers

Heat map for the expression values of differentially expressed OXPHOS proteins between dose groups is displayed using a green colour gradient for downregulated proteins, where dark green corresponds to large downregulation. The numbers shows how many proteins were deregulated in each subunit

Epidemiological studies show a significant increase in ischemic heart disease (IHD) incidence associated with total external gamma-ray dose among Mayak plutonium enrichment plant workers. Our previous studies using mouse models suggest that persistent alteration of heart metabolism due to the inhibition of peroxisome proliferator-activated receptor (PPAR) alpha accompanies cardiac damage after high doses of ionising radiation. The aim of the present study was to elucidate the mechanism of radiation-induced IHD in humans. The cardiac proteome response to irradiation was analysed in Mayak workers who were exposed only to external doses of gamma rays. All participants were diagnosed during their lifetime with IHD that also was the cause of death. Label-free quantitative proteomics analysis was performed on tissue samples from the cardiac left ventricles of individuals stratified into four radiation dose groups (0 Gy, <100 mGy, 100 - 500 mGy, and >500 mGy). The groups could be separated using principal component analysis based on all proteomics features. Proteome profiling showed a dose-dependent increase in the number of downregulated mitochondrial and structural proteins. Both proteomics and immunoblotting showed decreased expression of several oxidative stress responsive proteins in the irradiated hearts. The phosphorylation of transcription factor PPAR alpha was increased in a dose-dependent manner, which is indicative of a reduction in transcriptional activity with increased radiation dose. These data suggest that chronic external radiation enhances the risk for IHD by inhibiting PPAR alpha and altering the expression of mitochondrial, structural, and antioxidant components of the heart.

Publication:

Omid Azimzadeh, Tamara Azizova, Juliane Merl-Pham, Vikram Subramanian, Mayur V. Bakshi, Maria Moseeva, Olga Zubkova, Stefanie M. Hauck, Nataša Anastasov, Michael J. Atkinson, and Soile Tapio

A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers

Oncotarget. 2017 Feb 7;8(6):9067-9078. doi: 10.18632/oncotarget.10424.

 

Person to contact for further enquiries: PD Dr. Soile Tapio ; Tel : 3187-3445

Successful Cooperation in Gene Therapy

© cglightNing – Fotolia.com

The Helmholtz Zentrum München has been working with the company SIRION Biotech GmbH to optimize gene therapy applications since 2010. The new method of lentiviral transduction enhancement allows an efficient change of genes in stem cells and primary lymphocytes (B and T cells). Now the go-ahead has been given for a first gene therapy application in a phase III study, and the first major milestone payment has been made.

Gene therapy, which is the controlled replacement or repair of defective gene variants that pose a health threat, is one of the highest profile future technologies in global medical research. A high transduction rate is crucial for its success. This means the greatest possible efficiency when addressing cells in the body and genetically changing them in the desired way. The bottleneck here is usually the access to the cells: In the blood and primary cells that are important for the treatment, the success rates with traditional methods usually fall below 30 percent.

Experts at the Institute of Radiation Biology (ISB) at the Helmholtz Zentrum München and SIRION Biotech GmbH from Martinsried have therefore developed an efficient method to overcome this critical hurdle. By using so-called lentiviruses and new substances called non-toxic poloxamers, they were able to increase the success rate to over 80 percent. This method, called LentiBOOSTTM, significantly moves gene therapy forward on its way to market approval, according to the start-up company in a recent press release.

In dealings with various blood cells, academic institutions have already confirmed the efficiency of the technology, which was developed with substantial contributions from ISB scientists Dr. Nataša Anastasov, Dr. Ines Höfig and Prof. Michael J. Atkinson. The LentiBOOSTTM strategy is also already generating a great deal of interest in the industry. USA supervisory authorities recently gave the go-ahead for use of this so-called "Munich solution" in a broad-based phase III clinical study. SIRION Biotech accordingly received the first substantial, seven-digit milestone payment, which will also profit the Helmholtz Zentrum München thanks to a utilization agreement negotiated through Ascenion.

The use of lentiviruses in gene therapy is relevant for numerous approaches for the future, such as with the use of stem or CAR-T cells*. "We are really very happy that the technology has developed so well and that we can contribute to new therapeutic approaches," says Nataša Anastasov, project leader on the part of the Helmholtz Zentrum München.

Publications: SIRION Biotech GmbH: Breakthrough technology improves genetic stem cell therapies. Press release January 12, 2017.

Person to contact for further enquiries: Dr. Nataša Anastasov natasa.anastasov@helmholtz-muenchen.de; Tel : 3187-3798

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