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1. Utilizing patient-derived organoids of prostate cancer to predict functional homologous recombination repair deficiency and targeted therapy response

Author

Elsesy, M.E., primary, Oh-Hohenhorst, S.J., additional, Oing, C., additional, Eckhardt, A., additional, Burdak-Rothkamm, S., additional, Alawi, M., additional, Müller, C., additional, Schüller, U., additional, Maurer, T., additional, Von Amsberg, G., additional, Petersen, C., additional, Rothkamm, K., additional, and Mansour, W.Y., additional

Published
2024
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7. Comparison of Established and Emerging Biodosimetry Assays

Author

Rothkamm, K., Beinke, C., Romm, H., Badie, C., Balagurunathan, Y., Barnard, S., Bernard, N., Boulay-Greene, H., Brengues, M., De Amicis, A., De Sanctis, S., Greither, R., Herodin, F., Jones, A., Kabacik, S., Knie, T., Kulka, U., Lista, F., Martigne, P., Missel, A., Moquet, J., Oestreicher, U., Peinnequin, A., Poyot, T., Roessler, U., Scherthan, H., Terbrueggen, B., Thierens, H., Valente, M., Vral, A., Zenhausern, F., Meineke, V., Braselmann, H., and Abendb, M.

Published
2013
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11. Laboratory Intercomparison of Gene Expression Assays

Author

Badie, C., Kabacik, S., Balagurunathan, Y., Bernard, N., Brengues, M., Faggioni, G., Greither, R., Lista, F., Peinnequin, A., Poyot, T., Herodin, F., Missel, A., Terbrueggen, B., Zenhausern, F., Rothkamm, K., Meineke, V., Braselmann, H., Beinke, C., and Abend, M.

Published
2013
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12. Partial reduction in BRCA1 gene dose modulates DNA replication stress level and thereby contributes to sensitivity or resistance

Author

Classen, S. (Sandra), Rahlf, E. (Elena), Jungwirth, J. (Johannes), Albers, N. (Nina), Hebestreit, L. P. (Luca Philipp), Zielinski, A. (Alexandra), Poole, L. (Lena), Groth, M. (Marco), Koch, P. (Philipp), Liehr, T. (Thomas), Kankel, S. (Stefanie), Cordes, N. (Nils), Petersen, C. (Cordula), Rothkamm, K. (Kai), Pospiech, H. (Helmut), Borgmann, K. (Kerstin), Classen, S. (Sandra), Rahlf, E. (Elena), Jungwirth, J. (Johannes), Albers, N. (Nina), Hebestreit, L. P. (Luca Philipp), Zielinski, A. (Alexandra), Poole, L. (Lena), Groth, M. (Marco), Koch, P. (Philipp), Liehr, T. (Thomas), Kankel, S. (Stefanie), Cordes, N. (Nils), Petersen, C. (Cordula), Rothkamm, K. (Kai), Pospiech, H. (Helmut), and Borgmann, K. (Kerstin)

Abstract

BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.

Published
2022

13. Efficient DNA Repair Mitigates Replication Stress Resulting in Less Immunogenic Cytosolic DNA in Radioresistant Breast Cancer Stem Cells

Author

Meyer, F., M. Engel, A., K. Krause, A., Wagner, T., Poole, L., (0000-0002-3375-1500) Dubrovska, A., Peitzsch, C., Rothkamm, K., Petersen, C., Borgmann, K., Meyer, F., M. Engel, A., K. Krause, A., Wagner, T., Poole, L., (0000-0002-3375-1500) Dubrovska, A., Peitzsch, C., Rothkamm, K., Petersen, C., and Borgmann, K.

Abstract

Cancer stem cells (CSCs) are a major cause of tumor therapy failure. This is mainly attributed to increased DNA repair capacity and immune escape. Recent studies have shown that functional DNA repair via homologous recombination (HR) prevents radiation-induced accumulation of DNA in the cytoplasm, thereby inhibiting the intracellular immune response. However, it is unclear whether CSCs can suppress radiation-induced cytoplasmic dsDNA formation. Here, we show that the increased radioresistance of ALDH1-positive breast cancer stem cells (BCSCs) in S phase is mediated by both enhanced DNA double-strand break repair and improved replication fork protection due to HR. Both HR-mediated processes lead to suppression of radiation-induced replication stress and consequently reduction of cytoplasmic dsDNA. The amount of cytoplasmic dsDNA correlated significantly with BCSC content (p=0.0002). This clearly indicates that HR-dependent avoidance of radiation-induced replication stress mediates radioresistance and contributes to its immune evasion. Consistent with this, enhancement of replication stress by inhibition of ataxia telangiectasia and RAD3 related (ATR) resulted in significant radiosensitization (SER37 increase 1.7-2.8 Gy, p<0.0001). Therefore, disruption of HR-mediated processes, particularly in replication, opens a CSC-specific radiosensitization option by enhancing their intracellular immune response.

Published
2022

14. Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance

Author

Classen, S., Rahlf, E., Jungwirth, J., Albers, N., Hebestreit, L., Zielinski, A., Poole, L., Groth, M., Koch, P., Liehr, T., Kankel, S., (0000-0001-5684-629X) Cordes, N., Petersen, C., Rothkamm, K., Pospiech, H., Borgmann, K., Classen, S., Rahlf, E., Jungwirth, J., Albers, N., Hebestreit, L., Zielinski, A., Poole, L., Groth, M., Koch, P., Liehr, T., Kankel, S., (0000-0001-5684-629X) Cordes, N., Petersen, C., Rothkamm, K., Pospiech, H., and Borgmann, K.

Abstract

BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.

Published
2022

25. X-ray-Based Techniques to Study the Nano-Bio Interface

Author

Sanchez-Cano, C, Alvarez-Puebla, RA, Abendroth, JM, Beck, T, Blick, R, Cao, Y, Caruso, F, Chakraborty, I, Chapman, HN, Chen, C, Cohen, BE, Conceicao, ALC, Cormode, DP, Cui, D, Dawson, KA, Falkenberg, G, Fan, C, Feliu, N, Gao, M, Gargioni, E, Glueer, C-C, Gruener, F, Hassan, M, Hu, Y, Huang, Y, Huber, S, Huse, N, Kang, Y, Khademhosseini, A, Keller, TF, Koernig, C, Kotov, NA, Koziej, D, Liang, X-J, Liu, B, Liu, S, Liu, Y, Liu, Z, Liz-Marzan, LM, Ma, X, Machicote, A, Maison, W, Mancuso, AP, Megahed, S, Nickel, B, Otto, F, Palencia, C, Pascarelli, S, Pearson, A, Penate-Medina, O, Qi, B, Raedler, J, Richardson, JJ, Rosenhahn, A, Rothkamm, K, Rubhausen, M, Sanyal, MK, Schaak, RE, Schlemmer, H-P, Schmidt, M, Schmutzler, O, Schotten, T, Schulz, F, Sood, AK, Spiers, KM, Staufer, T, Stemer, DM, Stierle, A, Sun, X, Tsakanova, G, Weiss, PS, Weller, H, Westermeier, F, Xu, M, Yan, H, Zeng, Y, Zhao, Y, Zhu, D, Zhu, Y, Parak, WJ, Sanchez-Cano, C, Alvarez-Puebla, RA, Abendroth, JM, Beck, T, Blick, R, Cao, Y, Caruso, F, Chakraborty, I, Chapman, HN, Chen, C, Cohen, BE, Conceicao, ALC, Cormode, DP, Cui, D, Dawson, KA, Falkenberg, G, Fan, C, Feliu, N, Gao, M, Gargioni, E, Glueer, C-C, Gruener, F, Hassan, M, Hu, Y, Huang, Y, Huber, S, Huse, N, Kang, Y, Khademhosseini, A, Keller, TF, Koernig, C, Kotov, NA, Koziej, D, Liang, X-J, Liu, B, Liu, S, Liu, Y, Liu, Z, Liz-Marzan, LM, Ma, X, Machicote, A, Maison, W, Mancuso, AP, Megahed, S, Nickel, B, Otto, F, Palencia, C, Pascarelli, S, Pearson, A, Penate-Medina, O, Qi, B, Raedler, J, Richardson, JJ, Rosenhahn, A, Rothkamm, K, Rubhausen, M, Sanyal, MK, Schaak, RE, Schlemmer, H-P, Schmidt, M, Schmutzler, O, Schotten, T, Schulz, F, Sood, AK, Spiers, KM, Staufer, T, Stemer, DM, Stierle, A, Sun, X, Tsakanova, G, Weiss, PS, Weller, H, Westermeier, F, Xu, M, Yan, H, Zeng, Y, Zhao, Y, Zhu, D, Zhu, Y, and Parak, WJ

Abstract

X-ray-based analytics are routinely applied in many fields, including physics, chemistry, materials science, and engineering. The full potential of such techniques in the life sciences and medicine, however, has not yet been fully exploited. We highlight current and upcoming advances in this direction. We describe different X-ray-based methodologies (including those performed at synchrotron light sources and X-ray free-electron lasers) and their potentials for application to investigate the nano-bio interface. The discussion is predominantly guided by asking how such methods could better help to understand and to improve nanoparticle-based drug delivery, though the concepts also apply to nano-bio interactions in general. We discuss current limitations and how they might be overcome, particularly for future use in vivo.

Published
2021

36. Ex-vivo-Kulturen humaner HNSCC Tumoren bestätigen eine eingeschränkte DNA-Doppelstrangbruch-Reparatur HPV-positiver OPSCC und weisen auf einen Defekt der ATM-abhängigen Schadensantwort hin

Author

Zech, HB, additional, Betz, CS, additional, Kriegs, M, additional, Köcher, S, additional, Mansour, W, additional, Möckelmann, N, additional, Böttcher, A, additional, Busch, Chia-Jung, additional, Petersen, C, additional, Rothkamm, K, additional, and Rieckmann, T, additional

Published
2020
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37. Ex-vivo slice cultures of tumor tissues confirm the DNA double-strand break repair defect of HPV-positive OPSCC and suggest a defect in the ATM-mediated DNA damage response

Author

Zech, Henrike Barbara, additional, Betz, CS, additional, Kriegs, M, additional, Köcher, S, additional, Mansour, W, additional, Möckelmann, N, additional, Böttcher, A, additional, Busch, Chia-Jung, additional, Petersen, C, additional, Rothkamm, K, additional, and Rieckmann, T, additional

Published
2020
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44. Web based scoring is useful for validation and harmonisation of scoring criteria within RENEB

Author

Romm, H., Ainsbury, E.A., Barquinero, J.F., Barrios, L., Beinke, C., Cucu, A., Domene, M.M., Filippi, S., Monteiro Gil, O., Gregoire, E., Hadjidekova, V., Hatzi, V., Lindholm, C., M´kacher, R., Montoro, A., Moquet, J., Noditi, M., Oestreicher, U., Palitti, F., Pantelias, G., Prieto, M.J., Popescu, I., Rothkamm, K., Sebastià, N., Sommer, S., Terzoudi, G., Testa, A., Wojcik, A., University of Tuscia, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), National Centre for Scientific Research Demokritos, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hospital Universitario y Politécnico La Fe, Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile (ENEA), European Commission, EC 295513, Università degli studi della Tuscia [Viterbo], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, and Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile = Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA)

Subjects
Internet, [SDV]Life Sciences [q-bio], Web based scoring, Reproducibility of Results, Radiation Exposure, biological dosimetry, Sensitivity and Specificity, Europe, radiation, Radiation Monitoring, Cytogenetic Analysis, Humans, Biological Assay, Lymphocytes, biodosimetry network, Laboratories, dicentric assay
Abstract

International audience; Purpose To establish a training data set of digital images and to investigate the scoring criteria and dose assessment of the dicentric assay within the European network of biodosimetry (RENEB), a web based scoring inter-comparison was undertaken by 17 RENEB partners. Materials and methods Two sets of 50 high resolution images were uploaded onto the RENEB website. One set included metaphases after a moderate exposure (1.3 Gy) and the other set consisted of metaphases after a high dose exposure (3.5 Gy). The laboratories used their own calibration curves for estimating doses based on observed aberration frequencies. Results The dose estimations and 95% confidence limits were compared to the actual doses and the corresponding z-values were satisfactory for the majority; only the dose estimations from two laboratories were too low or too high. The coefficients of variation were 17.6% for the moderate and 11.2% for the high dose. Metaphases with controversial results could be identified for training purposes. Conclusions Overall, the web based scoring of the two galleries by the 17 laboratories produced very good results. Application of web based scoring for the dicentric assay may therefore be a relevant strategy for an operational biodosimetry assistance network. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor and Francis Group.

Published
2017

45. Interaktion von Stammzelleigenschaften und DNA Reparatur bestimmen die strahlensensitivierende Wirkung nach Inhibition von CHK1, RAD51 und PARP1 in TNBCs

Author

Meyer, F., Becker, S., Niecke, A., Werner, S., Peitzsch, C., Hein, L., Dubrovska, A., Goy, Y., Parplys, A., Petersen, C., Riepen, B., Zielinski, A., Rothkamm, K., and Borgmann, K.

Subjects
Mammakarzinom, DNA Reparaturweg, Homologe Rekombination (HR)
Abstract

Fragestellung: Das Mammakarzinom fasst eine heterogene Gruppe von Tumoren zusammen von denen etwa 20% als Triple-negativ (TNBC) bezüglich des Rezeptorstatus bezeichnet werden. Wichtige Parameter und therapeutische Angriffspunkte der TNBC Biologie sind eine hohe Proliferationsaktivität, ein Basal-artiger und mesenchymaler Phänotyp und ein Defekt im DNA Reparaturweg Homologe Rekombination (HR) welcher eine erhöhte chromosomale Instabilität dieser Tumore begünstigt. TNBCs weisen darüber hinaus eine Anreicherung von Tumorstammzellen und Therapieresistenz auf. Ziel des Projektes ist es Strategien unter gleichzeitiger Ausnutzung von HR-Defizienz und Stammzelleigenschaften durch spezifische Inhibition zur Intensivierung der Therapie weiter zu entwickeln. Dies wurde für die Inhibition von RAD51-, CHK1- und PARP1 nach Bestrahlung untersucht. Dafür wurde eine TNBC-Zelllinie (MDA-231 WT), zwei isogenen Sublinien, die präferentiell in Knochen (-SA) und Gehirn (-BR) metastasieren im Vergleich zu einer luminalen Zelllinie (MCF7) eingesetzt. Methodik: In MDA-MB-231 WT/BR/SA und MCF7-Zellen wurde die Expression bezüglich HR (RAD51, BRCA1, PTEN, CHK1, MRE11, ATR, ATM) und Stammzelleigenschaften (ZEB1, E-Cadherin, ß-Catenin, ALDH1) charakterisiert, HR mittels RAD51-Foci, MMC-Sensitivität und Reporterplasmiden eingeordnet, Replikationsprozesse analysiert und die Migrationsfähigkeit überprüft. Strahlenempfindlichkeit wurde unter Gabe verschiedener Inhibitoren im Kolonietest dokumentiert und mit der Metabric Datenbank (952 TNBC) hinsichtlich des chromosomalen Instabilitätsindex (CIN) korreliert. Ergebnisse: Es zeigten sich klare Unterschiede in der Expression von Reparaturproteinen, mit einem Anstieg von CHK1, MRE11 und ATM in BR und SA. Beide Linien zeigten Stammzell-übliche Expressionsprofile, entsprechend eine stärkere Migrationsfähigkeit und in der SA Linie eine verbesserte HR (2,5-fach), Resistenz gegen MMC (IC50 von 1,6µg/ml im Vergleich zu 0,75µg/ml in BR und 2,1 µg/ml in SA) und geringere DNA Schäden (0,75-fach). Nach Bestrahlung zeigte sich kein Überlebensvorteil für BR und SA. Dies deutet darauf hin, dass nicht HR, sondern übergeordnet CHK1-vermittelte Prozesse für die Strahlenempfindlichkeit verantwortlich sind. Bestätigt wird dies durch die deutliche Strahlensensitivierung nach CHK1i, wobei die strahlenresistenteste Linie sich am stärksten sensitivieren ließ, mit VF von 3. Dies spiegelt sich auch in den Replikationsprozessen wieder, je sensitiver, desto stärker inhibiert. Momentan wird der Einfluss weiterer Inhibitoren auf die zelluläre Strahlenempfindlichkeit überprüft. Topkandidat ist RAD51i, da in einer Metabric-Analyse TNBC mit hohem CIN, also besonders aggressiven Tumoren, RAD51 und CHK1 deutlich stärker exprimiert werden als in TNBCs mit niedrigem CIN. Schlussfolgerung: Eine veränderte Expression von HR-Proteinen und ein Stammzell-artiger Phänotyp hängen eng zusammen und determinieren gemeinsam die Therapieresistenz.

Published
2017

46. The RENEB operational basis : complement of established biodosimetric assays

Author

Wojcik, A., Oestreicher, U., Barrios, L., Vral, A., Terzoudi, G., Ainsbury, E., Rothkamm, K., Trompier, F., Kulka, U., Public Health England [London], and Institut de Radioprotection et de Sûreté Nucléaire (IRSN)

Subjects
Biological dosimetry, DAMAGE, dosimetry network, [SDV]Life Sciences [q-bio], Medicine and Health Sciences, Biology and Life Sciences, NETWORK, DOSIMETRY, EMERGENCY, radiation emergency, intercomparison
Abstract

International audience; Purpose To set up an operational basis of the Realizing the European Network of Biodosimetry (RENEB) network within which the application of seven established biodosimetric tools (the dicentric assay, the FISH assay, the micronucleus assay, the PCC assay, the gamma-H2AX assay, electron paramagnetic resonance and optically stimulated luminescence) will be compared and standardized among the participating laboratories. Methodology Two intercomparisons were organized where blood samples and smartphone components were irradiated, coded and sent out to participating laboratories for dosimetric analysis. Moreover, an accident exercise was organized during which each RENEB partner had the chance to practice the procedure of activating the network and to handle large amounts of dosimetric results. Results All activities were carried out as planned. Overall, the precision of dose estimates improved between intercomparisons 1 and 2, clearly showing the value of running such regular activities. Conclusions The RENEB network is fully operational and ready to act in case of a major radiation emergency. Moreover, the high capacity for analyzing radiation-induced damage in cells and personal electronic devices makes the network suitable for large-scale analyses of low doses effects, where high numbers of samples must be scored in order to detect weak effects. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor and Francis Group.

Published
2017

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