Center for Molecular Medicine Cologne

Schweiger, Michal-Ruth | Poepsel, Simon | Klußmann, Jens - A 12

Structure of the BRD4 stress complex and implications in HPV maintenance and therapy response

Inroduction

BRD4 is a potent target of chemotherapeutic treatments. To further improve the targeted therapeutic strategies a better knowledge of its structure and function in discrete contexts such as e.g. nuclear stress bodies (nSBs) is required.

Together with Dr. Poepsel and Prof. Klußmann we aim to perform mass spectrometry and structural analyses to explore context specific BRD4 interactions and BRD4 containing regulatory complexes, and investigate the consequences of a de-regulation of BRD4 on HNSCC tumor pathophysiology through papillomaviruses.

In the last decade the epigenetic sensor protein bromodomain protein 4 (BRD4) has been discovered as a valuable drug target in many tumor entities, including leukemia, lung cancer, multiple myeloma (MM) and melanoma. However, the exact mechanism of BRD4 inhibition as a powerful anti-cancer treatment is still unclear. Our work is based on the rationale that the ubiquitous epigenetic regulator BRD4 performs distinct biological functions depending on the local molecular context. Therefore, specifying the determinants of such contexts may help identifying interactions and functions that are particularly important in clinical scenarios.

Recently, we have shown that BRD4 interacts with heat shock factor 1 (HSF1), induces SatIII expression during heat shock and chemotherapeutic interventions and co-localizes with SatIII at nuclear stress bodies (nSBs).

We also found that an increase in SatIII expression induces chemotherapy resistance and inhibition of BRD4 with chemical compounds can revert this effect. These findings are clear indications of molecular players and processes involved in specific cancer- and stress-associated functions of BRD4. 

The aim of this project is to better understand BRD4’s functions at sites of nSB formation. We will use mass spectrometry, cryo-electron microscopy (cryo-EM) and functional analyses to gain insight into structural features of BRD4 interactions that define its function within nSB. In particular, we will investigate whether and how papillomaviruses can modify these structures and use it for its propagation. Consequences of this will be investigated in primary head and neck squamous cell carcinoma (HNSCC) tumors.

Knowledge about BRD4 function during the stress response will provide valuable means to optimize chemotherapeutic agents targeting BRD4 and to develop predictive biomarkers for HNSCC.

Our Aims

  1. Mass spectrometric analyses of BRD4 complexes under stress exposure and functional characterization of their effects on chromatin structure.
  2. Structural analysis of BRD4 containing complexes localized at nuclear stress bodies.
  3. Clinical consequences of disruption of the BRD4 complexes on i) therapy resistance, ii) papillomavirus infection and iii) head and neck squamous cell carcinomas (HNSCCs).

Previous Work

During our work on BRD4 we showed that BRD4 is a central part of the cellular stress response. It regulates the expression of the kelch like ECH associated protein 1 (KEAP1) and downstream nuclear factor erythroid 2 like 1 (NFE2L1) cytoprotective target genes. Furthermore, we found that during the heat stress response BRD4 interacts with the heat shock factor 1 (HSF1), co-localizes with HSF1 in nuclear stress bodies (nSB) and regulates Satellite SatIII RNA expression in an HSF1 dependent manner.

Satellites are repetitive sequences located at pericentromeric regions. An aberrant overexpression of SatIII together with decondensation and demethylation of pericentromeric DNA is found in numerous cancer entities and in genetic disorders such as Hutchinson-Gilford progeria. Furthermore, pericentromeric transcripts are involved in heterochromatin formation and genomic stability and might thus be a driving force in malignant transformation. During the heat and proteotoxic stress response, BRD4, HSF1 and SatIII RNA are localized at nSBs.

Within an independent string of research we had identified the papillomaviral protein E2 as BRD4 interacting partner. E2 binds to the C-terminal domain of BRD4, targets E2 to mitotic chromosomes and thereby ensures a faithful distribution of PV genomes to daughter cells. This might be in particular relevant for the development of HVP-related cancers such as cervical cancer and head and neck squamous cell carcinomas (HNSCC). HNSCC arise in the upper aerodigestive tract and infections with HPV have been recently implicated in its pathogenesis.

Specifically, carcinomas arising from the lymphoid tissue of the oropharynx are HPV-associated and they differ in clinical and molecular aspects compared to classical HNSCC. These differences are found for oncogenic pathways driven by genetic but also epigenetic changes. The incidence of this new virus-associated tumor entity is strongly increasing and now 50-80% of all oropharyngeal carcinomas are HPV16 positive. These patients have a significantly improved overall and disease-free survival compared with patients with HPV-negative diseases. They also present with an improved response rate to chemotherapies (including platin-derived chemotherapies).

The overall goal of the proposed project is to understanding BRD4’s function in HNSCC and to explore it as potential therapeutic target. This will open up new ways towards more rational BRD4-directed therapeutic interventions and the development of specific predictive biomarkers.

Description of the groups and their role within the project

The project benefits from the collaboration between three groups: The Department of Otorhinolaryngology, Head and Neck Surgery (Klussmann), the Laboratory of Structure and Biochemistry of Epigenetic Regulators (Poepsel) and the Institute for Translational Epigenetics (Schweiger).

The Schweiger group has long-standing experience in molecular biology and biochemistry as well as in the development and establishment of diverse epigenetic technologies including large-scale experiments and data analyses. A focus of the group are epigenetic regulations in cancer and their targeted disruption for cancer treatments.

The research of the Klussmann group focus on translational and clinical research on HPV-related head and neck cancer for many years. They have established large biobanks with detailed clinical data from patients with HPV-related and unrelated HNSCC.

The Poepsel Lab focuses on the regulation of chromatin modifying enzymes and the read-out of chromatin modifications such as histone acetylation and methylation, with a particular emphasis on how multi-protein complexes are targeted to and locally regulated at their genomic sites of action. Their expertise relevant for this project lies in the isolation, characterization and structural elucidation of chromatin associated complexes.

  1. Grimm C, Fischer A, Farrelly AM, Kalachand R, Castiglione R, Wasserburger E, Hussong M, Schultheis AM, Altmüller J, Thiele H, Reinhardt HC, Hauschulz K, Hennessy BT, Herwig R, Lienhard M, Buettner R, Schweiger MR.: Combined Targeted Resequencing of Cytosine DNA Methylation and Mutations of DNA Repair Genes with Potential Use for Poly(ADP-Ribose) Polymerase 1 Inhibitor Sensitivity Testing. J Mol Diagn. 2019 Mar;21(2):198-213.
  2. Herberg M, Siebert S, Quaas M, Thalheim T, Rother K, Hussong M, Altmüller J, Kerner C, Galle J*, Schweiger MR*, Aust G.*: Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine. Clin Epigenetics. 2019 Apr 27;11(1):65. *equally contributed
  3. Grasse S, Lienhard M, Frese S, Kerick M, Steinbach A, Grimm C, Hussong M, Rolff J, Becker M, Dreher F, Schirmer U, Boerno S, Ramisch A, Leschber G, Timmermann B, Grohé C, Lüders H, Vingron M, Fichtner I, Klein S, Odenthal M, Büttner R, Lehrach H, Sültmann H, Herwig R, Schweiger MR.: Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Med. 2018 Jul 20;10(1):55.
  4. Lienhard M, Grasse S, Rolff J, Frese S, Schirmer U, Becker M, Börno S, Timmermann B, Chavez L, Sültmann H, Leschber G, Fichtner I, Schweiger MR*, Herwig R.*: QSEA-modelling of genome-wide DNA methylation from sequencing enrichment experiments. Nucleic Acids Res. 2017 Apr 7;45(6) *equally contributed
  5. Hussong M, Kaehler C, Kerick M, Grimm C, Franz A, Timmermann B, Welzel F, Isensee J, Hucho T, Krobitsch S, Schweiger MR.: The bromodomain protein BRD4 regulates splicing during heat shock. Nucleic Acids Res. 2017 Jan 9;45(1):382-394.
  6. Hussong M, Börno ST, Kerick M, Wunderlich A, Franz A, Sültmann H, Timmermann B, Lehrach H, Hirsch-Kauffmann M, Schweiger MR:The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5:e1195.
  7. Schweiger, M. R., You, J. & Howley, P. M. Bromodomain protein 4 mediates the papillomavirus E2 transcriptional activation function. Journal of virology80, 4276-4285, doi:10.1128/JVI.80.9.4276-4285.2006 (2006).
  8. You, J., Schweiger, M. R. & Howley, P. M. Inhibition of E2 binding to Brd4 enhances viral genome loss and phenotypic reversion of bovine papillomavirus-transformed cells. Journal of virology79, 14956-14961, doi:10.1128/JVI.79.23.14956-14961.2005 (2005).
  9. Reder H, Wagner S, Gamerdinger U, Sandmann S, Wuerdemann N, Braeuninger A, Dugas M, Gattenloehner S, Klussmann JP, Wittekindt C. Genetic alterations in human papillomavirus-associated oropharyngeal squamous cell carcinoma of patients with treatment failure. Oral Oncol. 2019 Jun;93:59-65.
  10. Wittekindt C, Wagner S, Bushnak A, Prigge ES, von Knebel Doeberitz M, Würdemann N, Bernhardt K, Pons-Kühnemann J, Maulbecker-Armstrong C, Klussmann JP. Increasing Incidence rates of Oropharyngeal Squamous Cell Carcinoma in Germany and Significance of Disease Burden Attributed to Human Papillomavirus. Cancer Prev Res (Phila). 2019 Jun;12(6):375-382.
  11. Huebbers CU, Verhees F, Poluschkin L, Olthof NC, Kolligs J, Siefer OG, Henfling M, Ramaekers FCS, Preuss SF, Beutner D, Seehawer J, Drebber U, Korkmaz Y, Lam WL, Vucic EA, Kremer B, Klussmann JP, Speel EM. Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV-negative tumors is an indicator of poor prognosis. Int J Cancer. 2019 May 15;144(10):2465-2477.
  12. Knuth J, Sharma SJ, Würdemann N, Holler C, Garvalov BK, Acker T, Wittekindt C, Wagner S, Klussmann JP. Hypoxia-inducible factor-1α activation in HPV-positive head and neck squamous cell carcinoma cell lines. Oncotarget. 2017 Sep 11;8(52):89681-89691.
  13. Poepsel, S., Kasinath, V., & Nogales, E. (2018). Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes. Nature Structural & Molecular Biology,25,154–162.
  14. Kasinath, V., Faini, M., Poepsel, S., Reif, D., Feng, X. A., … Nogales, E. (2018). Structures of human PRC2 with its cofactors AEBP2 and JARID2. Science, 359(6378), 940–944
  • Grimm C, Herling CD, Komnidi A, Hussong M, Kreuzer KA, Hallek M, Schweiger MR. (2022). Evaluation of a Prognostic Epigenetic Classification System in Chronic Lymphocytic Leukemia Patients. Biomark Insights. Doi: 10.1177/11772719211067972
  • Alipour S, Pick C, Jansen S, Rink S, Klußmann JP, Grosheva M. (2021). Long-term therapy with botulinum toxin in facial synkinesis: Retrospective data analysis of data from 1998 to 2018. Clin Otolaryngol. 2021 Jul;46(4):758-766. doi: 10.1111/coa.13729.
  • Kanne J, Hussong M, Isensee J, Munoz-Lopez A, Wolffgramm J, Hess F, Grimm C, Bessonov S, Meder L, Wang J, Reinhardt HC, Odenthal M, Hucho T, Buttner R, Summerer D, and Schweiger MR (2021). Pericentromeric Satellite III transcripts induce etoposide resistance. Cell Death Dis12, 530. doi:10.1038/s41419-021-03810-9.
                                                                                                    • Pacholewska A, Grimm C, Herling CD, Lienhard M, Konigs A, Timmermann B, Altmuller J, Mucke O, Reinhardt HC, Plass C, Herwig R, Hallek M, and Schweiger MR (2021). Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients. Int J Mol Sci22. doi:10.3390/ijms22179337.
                                                                                                              • Perne C, Peters S, Cartolano M, Horpaopan S, Grimm C, Altmuller J, Sommer AK, Hillmer AM, Thiele H, Odenthal M, Moslein G, Adam R, Sivalingam S, Kirfel J, Schweiger MR, Peifer M, Spier I, and Aretz S (2021). Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis. PLoS One16, e0259185. doi:10.1371/journal.pone.0259185.
                                                                                                                                                                                                    • Thalheim T, Siebert S, Quaas M, Herberg M, Schweiger MR, Aust G, and Galle J (2021). Epigenetic Drifts during Long-Term Intestinal Organoid Culture. Cells10. doi:10.3390/cells10071718.
                                                                                                                                                                                                    • Kasinath V, Beck C, Sauer P, Poepsel S, Kosmatka J, Faini M, Toso D, Aebersold R, and Nogales E (2021). JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications. Science371. doi:10.1126/science.abc3393.
                                                                                                                                                                                                          • Arolt C, Hoffmann F, Nachtsheim L, Wolber P, Guntinas-Lichius O, Buettner R, von Eggeling F, Quaas A, and Klussmann JP (2021). Mutually Exclusive Expression of COL11A1 by CAFs and Tumour Cells in a Large panCancer and a Salivary Gland Carcinoma Cohort. Head Neck Pathol. doi:10.1007/s12105-021-01370-0.
                                                                                                                                                                                                          • Klein S, Quaas A, Quantius J, Loser H, Meinel J, Peifer M, Wagner S, Gattenlohner S, Wittekindt C, von Knebel Doeberitz M, Prigge ES, Langer C, Noh KW, Maltseva M, Reinhardt HC,Buttner R, Klussmann JP, and Wuerdemann N (2021). Deep Learning Predicts HPV Association in Oropharyngeal Squamous Cell Carcinomas and Identifies Patients with a Favorable Prognosis Using Regular H&E Stains. Clin Cancer Res27, 1131-1138. doi:10.1158/1078-0432.CCR-20-3596.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            • Otte MS, Bork ML, Zimmermann PH, Klussmann JP, and Luers JC (2021). Patients with COVID-19-associated olfactory impairment also show impaired trigeminal function. Auris Nasus Larynx. doi:10.1016/j.anl.2021.07.012.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            • Otte MS, Bork ML, Zimmermann PH, Klussmann JP, and Luers JC (2021). Persisting olfactory dysfunction improves in patients 6 months after COVID-19 disease. Acta Otolaryngol141, 626-629. doi:10.1080/00016489.2021.1905178.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Reder H, Wagner S, Wuerdemann N, Langer C, Sandmann S, Braeuninger A, Dugas M, Gattenloehner S, Wittekindt C, and Klussmann JP (2021). Mutation patterns in recurrent and/or metastatic oropharyngeal squamous cell carcinomas in relation to human papillomavirus status. Cancer Med10, 1347-1356. doi:10.1002/cam4.3741.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Thelen M, Wennhold K, Lehmann J, Garcia-Marquez M, Klein S, Kochen E, Lohneis P, Lechner A, Wagener-Ryczek S, Plum PS, Velazquez Camacho O, Pfister D, Dorr F, Heldwein M, Hekmat K, Beutner D, Klussmann JP, Thangarajah F, Ratiu D, Malter W, Merkelbach-Bruse S, Bruns CJ, Quaas A, von Bergwelt-Baildon M, and Schlosser HA (2021). Cancer-specific immune evasion and substantial heterogeneity within cancer types provide evidence for personalized immunotherapy. NPJ Precis Oncol5, 52. doi:10.1038/s41698-021-00196-x.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Uzun S, Korkmaz Y, Wuerdemann N, Arolt C, Puladi B, Siefer OG, Donmez HG, Hufbauer M, Akgul B, Klussmann JP, and Huebbers CU (2021). Comprehensive Analysis of VEGFR2 Expression in HPV-Positive and -Negative OPSCC Reveals Differing VEGFR2 Expression Patterns. Cancers (Basel)13. doi:10.3390/cancers13205221.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Wolber P, Nachtsheim L, Hoffmann F, Klussmann JP, Meyer M, von Eggeling F, Guntinas-Lichius O, Quaas A, and Arolt C (2021). Trophoblast Cell Surface Antigen 2 (Trop-2) Protein is Highly Expressed in Salivary Gland Carcinomas and Represents a Potential Therapeutic Target. Head Neck Pathol15, 1147-1155. doi:10.1007/s12105-021-01325-5.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Zimmermann PH, Stuut M, Wuerdemann N, Mollenhoff K, Suchan M, Eckel H, Wolber P, Sharma SJ, Kammerer F, Langer C, Wittekindt C, Wagner S, Kremer B, Speel EJM, and Klussmann JP (2021). Upfront Surgery vs. Primary Chemoradiation in an Unselected, Bicentric Patient Cohort with Oropharyngeal Squamous Cell Carcinoma-A Matched-Pair Analysis. Cancers (Basel)13. doi:10.3390/cancers13215265.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Balaji H, Demers I, Wuerdemann N, Schrijnder J, Kremer B, Klussmann JP, Huebbers CU, and Speel EM (2021). Causes and Consequences of HPV Integration in Head and Neck Squamous Cell Carcinomas: State of the Art. Cancers (Basel)13. doi:10.3390/cancers13164089.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Boedicker C, Hussong M, Grimm C, Dolgikh N, Meister MT, Enssle JC, Wanior M, Knapp S, Schweiger MR, and Fulda S (2020). Co-inhibition of BET proteins and PI3Kalpha triggers mitochondrial apoptosis in rhabdomyosarcoma cells. Oncogene 39, 3837-52.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Nattramilarasu PK, Bucker R, Lobo de Sa FD, Fromm A, Nagel O, Lee IM, Butkevych E, Mousavi S, Genger C, Klove S, Heimesaat MM, Bereswill S, Schweiger MR, Nielsen HL, Troeger H, and Schulzke JD (2020). Campylobacter concisus Impairs Sodium Absorption in Colonic Epithelium via ENaC Dysfunction and Claudin-8 Disruption. Int J Mol Sci 21.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Thalheim T, Hopp L, Herberg M, Siebert S, Kerner C, Quaas M, Schweiger MR, Aust G, and Galle J (2020). Fighting Against Promoter DNA Hyper-Methylation: Protective Histone Modification Profiles of Stress-Resistant Intestinal Stem Cells. Int J Mol Sci 21.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Otte MS, Eckel HNC, Poluschkin L, Klussmann JP, and Luers JC (2020). Olfactory dysfunction in patients after recovering from COVID-19. Acta oto-laryngologica 10.1080/00016489.2020.1811999, 1-4.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Pinatti LM, Walline HM, Carey TE, Klussmann JP, and Huebbers CU (2020). Viral Integration Analysis Reveals Likely Common Clonal Origin of Bilateral HPV16-Positive, p16-Positive Tonsil Tumors. Archives of clinical and medical case reports 4, 680-96.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Reder H, Taferner VF, Wittekindt C, Brauninger A, Speel EM, Gattenlohner S, Wolf G, Klussmann JP, Wuerdemann N, and Wagner S (2020). Plasma Cell-Free Human Papillomavirus Oncogene E6 and E7 DNA Predicts Outcome in Oropharyngeal Squamous Cell Carcinoma. The Journal of molecular diagnostics : JMD 10.1016/j.jmoldx.2020.08.002.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Wuerdemann N, Gultekin SE, Putz K, Wittekindt C, Huebbers CU, Sharma SJ, Eckel H, Schubotz AB, Gattenlohner S, Buttner R, Speel EJ, Klussmann JP, Wagner S, and Quaas A (2020a). PD-L1 Expression and a High Tumor Infiltrate of CD8+ Lymphocytes Predict Outcome in Patients with Oropharyngeal Squamous Cells Carcinoma. Int J Mol Sci 21.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Wuerdemann N, Jain R, Adams A, Speel EM, Wagner S, Joosse SA, and Klussmann JP (2020b). Cell-Free HPV-DNA as a Biomarker for Oropharyngeal Squamous Cell Carcinoma-A Step Towards Personalized Medicine? Cancers (Basel) 12.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  • Wuerdemann N, Putz K, Eckel H, Jain R, Wittekindt C, Huebbers CU, Sharma SJ, Langer C, Gattenlohner S, Buttner R, Speel EJ, Suchan M, Wagner S, Quaas A, and Klussmann JP (2020c). LAG-3, TIM-3 and VISTA Expression on Tumor-Infiltrating Lymphocytes in Oropharyngeal Squamous Cell Carcinoma-Potential Biomarkers for Targeted Therapy Concepts. Int J Mol Sci 22.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Prof. Dr. Dr. Michal-Ruth Schweiger CMMC Cologne
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Prof. Dr. Dr. Michal-Ruth Schweiger

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Institute for Translational Epigenomics

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  +49 221 478 96846

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Dr. Simon Pöpsel CMMC Cologne
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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Prof. Dr. Jens P Klussmann CMMC Cologne
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Prof. Dr. Jens P Klussmann

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Dr. Maria Grosheva
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Christian Hübbers
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Christopher Kopp
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Margaret Maltseva
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Dr. Shachi Jenny Sharma
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Oliver Siefer
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Malte Suchan
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Nora Würdemann
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Philipp Zimmermann