Robert Paul Coppes
@rug.nl/umcg
University Medical Center Groningen, Departments of Biomedical Sciences of Cells & System and Radiation Oncology
University Medical Center Groningen
2019-present Editorial Board Member of Cancers
2018-present Member of Scientific Advisory Board of the Helmholtz-Zentrum Dresden-Rossendorf Germany
2018-present Member of the UMCG Appointment Advisory Committee for academic promotions
2016-present Editorial Board Member Stem Cells
2016-present Member of the Scientific Council of the European Society of Radiotherapy and Oncology (ESTRO)
2015-2021 Chair of the Radiobiology Committee of ESTRO.
2015-present Editor Biology of Radiotherapy and Oncology, Journal of ESTRO.
2015-2021 Associate senior editor of the International Journal of Radiation Oncology*Biology*Physics.
2014-present Faculty at ESTRO Basic Clinical Radiobiology course
2014-present Chair of the Animal Welfare Body of the University of Groningen, Centre of Life Sciences
2013-present Programme leader of Cancer Research Center Groningen (CRCG) research ; Damage and Repair in Cancer Development and Cancer Treatment (DARE)
2012-present Full Professor of Radiotherapy
EDUCATION
1993-1998 Post-doctoral training in clinical radiation biology. Dept Radiobiology, University of Groningen, The Netherlands
1993 PhD in Molecular Pharmacology, Faculty of Mathematics and Natural Sciences, University of Groningen, The Netherlands
1988 MSc in Biology, University of Groningen
RESEARCH INTERESTS
Radiotherapy is involved in 75% of all cancer treatments. The dose that can be delivered to the tumor however is limited to the tolerance of the surrounding normal tissues. Therefore, the Coppes lab focuses on the effects of radiation on normal tissues in vivo and in vitro organoid models.
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Felix Broghammer, Irina Korovina, Mahesh Gouda, Martina Celotti, Johan van Es, Inga Lange, Cornelia Brunner, Jovan Mircetic, Robert P. Coppes, Olivier Gires,et al.
Springer Science and Business Media LLC
Abstract Background Focal adhesion signaling involving receptor tyrosine kinases (RTK) and integrins co-controls cancer cell survival and therapy resistance. However, co-dependencies between these receptors and therapeutically exploitable vulnerabilities remain largely elusive in HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods The cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin was determined in up to 20 3D matrix-grown HNSCC cell models followed by drug screening and patient-derived organoid validation. RNA sequencing and protein-based biochemical assays were performed for molecular characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. Results Fibroblast growth factor receptor (FGFR 1–4) targeting exhibited the strongest cytotoxic and radiosensitizing effects as monotherapy and combined with β1 integrin inhibition, exceeding the efficacy of the other RTK studied. Pharmacological pan-FGFR inhibition elicited responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence analysis revealed a mesenchymal-to-epithelial transition (MET) in sensitive cell models, whereas resistant cell models exhibited a partial epithelial-to-mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid-dependently. Transferring the EMT-associated transcriptomic profiles to HNSCC patient cohorts not only demonstrated their prognostic value but also provided a conclusive validation of the presence of EGFR-related vulnerabilities that can be strategically exploited for therapeutic interventions. Conclusions This study demonstrates that pan-FGFR inhibition elicits a beneficial radiochemosensitizing and a detrimental radioprotective potential in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically.
Daniëlle C. Voshart, Myrthe Klaver, Yuting Jiang, Hilmar R.J. van Weering, Fleur van Buuren-Broek, Gideon P. van der Linden, Davide Cinat, Harry H. Kiewiet, Justin Malimban, Daniel A. Vazquez-Matias,et al.
Elsevier BV
Daniëlle C. Voshart, Takuya Oshima, Yuting Jiang, Gideon P. van der Linden, Anna P. Ainslie, Luiza Reali Nazario, Fleur van Buuren-Broek, Ayla C. Scholma, Hilmar R.J. van Weering, Nieske Brouwer,et al.
Elsevier BV
Michael Baumann, Carol Bacchus, Marianne C. Aznar, Rob P. Coppes, Eric Deutsch, Dietmar Georg, Karin Haustermans, Peter Hoskin, Mechthild Krause, Eric F. Lartigau,et al.
Elsevier BV
Davide Cinat, Anna Lena De Souza, Abel Soto-Gamez, Anne L. Jellema-de Bruin, Rob P. Coppes, and Lara Barazzuol
Elsevier BV
A. Soto-Gamez, M. van Es, E. Hageman, S.A. Serna-Salas, H. Moshage, M. Demaria, S. Pringle, and R.P. Coppes
Elsevier BV
Michael Baumann, Carol Bacchus, Marianne C. Aznar, Rob P. Coppes, Eric Deutsch, Dietmar Georg, Karin Haustermans, Peter Hoskin, Mechthild Krause, Eric F. Lartigau,et al.
Elsevier BV
Frank Verhaegen, Karl T Butterworth, Anthony J Chalmers, Rob P Coppes, Dirk de Ruysscher, Sophie Dobiasch, John D Fenwick, Patrick V Granton, Stefan H J Heijmans, Mark A Hill,et al.
IOP Publishing
Abstract This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.
José M. Horcas-Nieto, Christian J. Versloot, Miriam Langelaar-Makkinje, Albert Gerding, Tjasso Blokzijl, Mirjam H. Koster, Mirjam Baanstra, Ingrid A. Martini, Robert P. Coppes, Céline Bourdon,et al.
Elsevier BV
Paulien Schaafsma, Laura Kracht, Mirjam Baanstra, Anne L. Jellema-de Bruin, and Robert P. Coppes
Frontiers Media SA
Human salivary gland organoids have opened tremendous possibilities for regenerative medicine in patients undergoing radiotherapy for the treatment of head and neck cancer. However, their clinical translation is greatly limited by the current use of Matrigel for organoid derivation and expansion. Here, we envisage that the use of a fully, synthetic hydrogel based on the oligo (-ethylene glycol) functionalized polymer polyisocyanopeptides (PICs) can provide an environment suitable for the generation and expansion of salivary gland organoids (SGOs) after optimization of PIC polymer properties. We demonstrate that PIC hydrogels decorated with the cell-binding peptide RGD allow SGO formation from salivary gland (SG)-derived stem cells. This self-renewal potential is preserved for only 4 passages. It was found that SGOs differentiated prematurely in PIC hydrogels affecting their self-renewal capacity. Similarly, SGOs show decreased expression of immediate early genes (IEGs) after culture in PIC hydrogels. Activation of multiple signalling pathways involved in IEG expression by β-adrenergic agonist isoproterenol, led to increased stem cell self-renewal capacity as measured by organoid forming efficiency (OFE). These results indicate that PIC hydrogels are promising 3D matrices for SGOs, with the option to be used clinically, after further optimization of the hydrogel and culture conditions.
Birgitte Vrou Offersen, Marianne C. Aznar, Carol Bacchus, Rob P. Coppes, Eric Deutsch, Dieter Georg, Karin Haustermans, Peter Hoskin, Mechthild Krause, Eric F. Lartigau,et al.
Elsevier BV
Madelon J. H. Metman, Pascal K. C. Jonker, Luc H. J. Sondorp, Bettien M. van Hemel, Mark S. Sywak, Anthony J. Gill, Liesbeth Jansen, Paul J. van Diest, Tessa M. van Ginhoven, Clemens W. G. M. Löwik,et al.
Springer Science and Business Media LLC
Abstract Purpose Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection. Methods A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy. Results Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg (n = 1), 0.13 mg/kg (n = 8), or 0.18 mg/kg (n = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound. Conclusion EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease. Trial registration NCT03470259
Milou E. Noltes, Luc H.J. Sondorp, Laura Kracht, Inês F. Antunes, René Wardenaar, Wendy Kelder, Annelies Kemper, Wiktor Szymanski, Wouter T. Zandee, Liesbeth Jansen,et al.
Elsevier BV
Roel J.H.M. Steenbakkers, Maria I. van Rijn – Dekker, Monique A. Stokman, Roel G.J. Kierkels, Arjen van der Schaaf, Johanna G.M. van den Hoek, Hendrik P. Bijl, Maria C.A. Kramer, Rob P. Coppes, Johannes A. Langendijk,et al.
Elsevier BV
Paola Serrano Martinez, Martti Maimets, Reinier Bron, Ronald van Os, Gerald de Haan, Sarah Pringle, and Robert P. Coppes
Elsevier BV
Marie-Catherine Vozenin, Andreas Schüller, Marie Dutreix, Karen Kirkby, Michael Baumann, Rob P. Coppes, and David Thwaites
Elsevier BV
P. K. Jonker, M. Metman, Luc Sondorp, M. Sywak, A. Gill, L. Jansen, T. Links, P. V. van Diest, T. V. van Ginhoven, C. Löwik,et al.
Patients undergoing prophylactic central compartment dissection (PCLND) for papillary thyroid cancer (PTC) are often overtreated. This study aimed to determine if molecular fluorescence-guided imaging (MFGI) and spectroscopy can be useful for detecting PTC nodal metastases (NM) and to identify negative central compartments intraoperatively. We used a data-driven prioritization strategy based on transcriptomic profiles of 97 primary PTCs and 80 normal thyroid tissues (NTT) to identify tumor-specific antigens for a clinically available near-infrared fluorescent tracer. Protein expression of the top prioritized antigen was immunohistochemically validated with a tissue microarray containing primary PTC (n = 741) and NTT (n = 108). Staining intensity was correlated with 10-year locoregional recurrence-free survival (LRFS). A phase 1 study (NCT03470259) with EMI-137, targeting MET, was conducted to evaluate safety, optimal dosage for detecting PTC NM with MFGI, feasibility of NM detection with quantitative fiber-optic spectroscopy, and selective binding of EMI-137 for MET. MET was selected as the most promising antigen. A worse LRFS was observed in patients with positive versus negative MET staining (81.9% versus 93.2%; p = 0.02). In 19 patients, no adverse events related to EMI-137 occurred. 0.13 mg/kg EMI-137 was selected as optimal dosage for differentiating NM from normal lymph nodes using MFGI (p < 0.0001) and spectroscopy (p < 0.0001). MFGI identified 5/19 levels (26.3%) without NM. EMI-137 binds selectively to MET. MET is overexpressed in PTC and associated with increased locoregional recurrence rates. Perioperative administration of EMI-137 is safe and facilitates NM detection using MFGI and spectroscopy, potentially reducing the number of negative PCLNDs with more than 25%. NCT03470259.
Julia Wiedemann, Robert P. Coppes, and Peter van Luijk
Frontiers Media SA
Radiotherapy is part of the treatment for many thoracic cancers. During this treatment heart and lung tissue can often receive considerable doses of radiation. Doses to the heart can potentially lead to cardiac effects such as pericarditis and myocardial fibrosis. Common side effects after lung irradiation are pneumonitis and pulmonary fibrosis. It has also been shown that lung irradiation has effects on cardiac function. In a rat model lung irradiation caused remodeling of the pulmonary vasculature increasing resistance of the pulmonary vascular bed, leading to enhanced pulmonary artery pressure, right ventricle hypertrophy and reduced right ventricle performance. Even more pronounced effects are observed when both, lung and heart are irradiated.The effects observed after lung irradiation show striking similarities with symptoms of pulmonary arterial hypertension. In particular, the vascular remodeling in lung tissue seems to have similar underlying features. Here, we discuss the similarities and differences of vascular remodeling observed after thoracic irradiation compared to those in pulmonary arterial hypertension patients and research models. We will also assess how this knowledge of similarities could potentially be translated into interventions which would be beneficial for patients treated for thoracic tumors, where dose to lung tissue is often unavoidable.
Roel J.H.M. Steenbakkers, Maria I. van Rijn-Dekker, Monique A. Stokman, Arjen van der Schaaf, Johanna G.M. van den Hoek, Hendrik P. Bijl, Maria C.A. Kramer, Johannes A. Langendijk, Peter van Luijk, Roel G.J. Kierkels,et al.
Elsevier BV
Vivian M.L. Ogundipe, John T.M. Plukker, Thera P. Links, and Rob P. Coppes
Mary Ann Liebert Inc
The incidence of treatment of thyroid disease and consequential hypothyroidism has been increasing over the past few years. To maintain adequate thyroid hormone levels, these patients require daily supplementation with levothyroxine (L-T4) for the rest of their lives. However, a large part of these patients experiences difficulties due to the medication, which causes a decrease in their quality of life. Regenerative medicine through tissue engineering could provide a potential therapy by establishing tissue engineering models, such as those employing thyroid-derived organoids. The development of such treatment options may replace the need for additional hormonal replacement therapy. This review aims to highlight the current knowledge on thyroid regenerative medicine using organoids for tissue engineering, and to discuss insights into potential methods to optimize thyroid engineering culture systems. Finally, we will describe several challenges faced when utilising these models.
Hongmei Dong, L. Du, Song-wang Cai, Wan Lin, Chaoying Chen, Matthew Still, Zhimeng Yao, R. Coppes, Yunlong Pan, Dianzheng Zhang,et al.
Despite the initial benefit from treating ERBB2-positive breast cancer with tyrosine kinase inhibitor lapatinib, resistance develops inevitably. Since the expression of protein tyrosine phosphatase receptor-type O (PTPRO), a member of the R3 subfamily of receptor protein tyrosine phosphatases (PTPs), is inversely correlated with the aggressiveness of multiple malignancies, we decided to explore the correlation between PTPRO and lapatinib resistance in ERBB2-positive breast cancer. Results of immunohistochemical (IHC) staining and the correlation analysis between the expression levels of PTPRO and the clinicopathological parameters indicate that PTPRO is downregulated in cancer tissues as compared with normal tissues and negatively associated with differentiation, tumor size, tumor depth, as well as the expression of ERBB2 and Ki67. Results from Kaplan–Meier analyses indicate that lower expression of PTPRO is correlated with shorter relapse-free survival for patients with ERBB2-positive breast cancer, and multivariable Cox regression analysis found that PTPRO can potentially serve as an independent prognostic indicator for ERBB2-positive breast cancer. Results from both human breast cancer cells with PTPRO knockdown or overexpression and mouse embryonic fibroblasts (MEFs) which derived from Ptpro +/+ and Ptpro −/− mice with then stably transfected plasmid FUGW-Erbb2 consistently demonstrated the essentiality of PTPRO in the lapatinib-mediated anticancer process. Our findings suggest that PTPRO is not only able to serve as an independent prognostic indicator, but upregulating PTPRO can also reverse the lapatinib resistance of ERBB2-positive breast cancer.
Liang Du, Da Wang, Peter W. Nagle, Andries A. H. Groen, Hao Zhang, Christina T. Muijs, John Th. M. Plukker, and Robert P. Coppes
MDPI AG
Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis. Therapy resistance and early recurrences are major obstacles in reaching a better outcome. Esophageal cancer stem-like cells (CSCs) seem tightly related with chemoradiation resistance, initiating new tumors and metastases. Several oncogenic pathways seem to be involved in the regulation of esophageal CSCs and might harbor novel therapeutic targets to eliminate CSCs. Previously, we identified a subpopulation of EC cells that express high levels of CD44 and low levels of CD24 (CD44+/CD24−), show CSC characteristics and reside in hypoxic niches. Here, we aim to clarify the role of the hypoxia-responding mammalian target of the rapamycin (mTOR) pathway in esophageal CSCs. We showed that under a low-oxygen culture condition and nutrient deprivation, the CD44+/CD24− population is enriched. Since both low oxygen and nutrient deprivation may inhibit the mTOR pathway, we next chemically inhibited the mTOR pathway using Torin-1. Torin-1 upregulated SOX2 resulted in an enrichment of the CD44+/CD24− population and increased sphere formation potential. In contrast, stimulation of the mTOR pathway using MHY1485 induced the opposite effects. In addition, Torin-1 increased autophagic activity, while MHY1485 suppressed autophagy. Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Finally, a clearly defined CD44+/CD24− CSC population was detected in EC patients-derived organoids (ec-PDOs) and here, MHY1485 also reduced this population. These data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. Stimulation of the mTOR pathway might aid in the elimination of putative esophageal CSCs.
R. Steenbakkers, Maria I. van Rijn-Dekker, M. Stokman, R. Kierkels, A. van der Schaaf, J. G. van den Hoek, H. Bijl, Maria C.A. Kramer, R. Coppes, J. Langendijk and P. van Luijk
Roel J.H.M. Steenbakkers, Maria I. van Rijn–Dekker, Monique A. Stokman, Roel G.J. Kierkels, Arjen van der Schaaf, Johanna G.M. van den Hoek, Hendrik P. Bijl, Maria C.A. Kramer, Robert P. Coppes, Johannes A. Langendijk,et al.
Elsevier BV