LUMC

Sylvie Noordermeer obtained her PhD in 2012 at the Radboud University Medical Center in Nijmegen. Her PhD research focussed on the process of ubiquitylation in acute myeloid leukemia (AML). A key finding during her PhD research was that overexpression of BRE – a protein interacting with BRCA1 –has prognostic value in AML and breast cancer. Funded by fellowships by the Canadian Terry Fox foundation and the Dutch Cancer Foundation (KWF), Sylvie continued her career as a postdoctoral fellow in the laboratory of Daniel Durocher in Toronto, Canada (2012-2016) and in the group of Haico van Attikum at the Leiden University Medical Center (2017-2018). During her postdoc, she worked on the molecular determinants of DNA double strand break repair. Key findings included the USP11-mediated regulation of homologous recombination during the cell cycle and the discovery of the Shieldin complex as an active inhibitor of resection during DNA double strand break repair.

In 2019, Sylvie started an independent research group at the Department of Human Genetics at the Leiden University Medical Center. With grants from the Dutch Research Council (NWO), the Dutch cancer foundation (KWF) and Oncode, her group studies BRCA1 protein complex formation and function during DNA double strand break repair. The primary research aims of the group are to better understand the molecular regulation of repair of DNA double stranded breaks and to improve the prediction of cancer onset and therapy response for patients carrying mutations in factors involved in DNA double strand break repair.

• 2020: project grant from the Dutch cancer foundation (KWF);

• 2019: VIDI grant from the Dutch Research Council (NWO);

• 2019: Oncode Young Investigator grant;

• 2019: C.J. Kok prize; a yearly prize awarded to the best fundamental scientist within the LUMC.

• 2018: Contribution from the LUMC Zaaijer Fund to encourage female scientists to apply for large research grants.

• 2014: Dutch Cancer Foundation (Koninklijk Wilhelmina Fonds) fellowship; a four-year fellowship covering personal funding and research allowance.

• 2012: Excellence in Radiation Research for the 21st century; a two-year fellowship covering personal funding by the Terry Fox Foundation and the Canadian Institute for Health Research (CIHR).

1. The Shieldin complex mediates 53BP1-dependent DNA repair. Nature, 2018 Aug; 560(7716).
   Noordermeer SM*, Adam S*, Setiaputra D*, Barazas M, Pettitt SJ, Ling AK, Olivieri M, Álvarez-Quilón A, Moatti N, Zimmermann M, Annunziato S, Krastev DB, Song F, Brandsma I, Frankum J, Brough R, Sherker A, Landry S, Szilard RK, Munro MM, McEwan A, Goullet de Rugy T, Lin ZY, Hart T, Moffat J, Gingras AC, Martin A, Van Attikum H, Jonkers J, Lord CJ, Rottenberg S, Durocher D.

2. A mechanism for the suppression of homologous recombination in G1 cells. Nature, 2015 Dec; 528(7582).
   Orthwein A*, Noordermeer SM*, Wilson MD, Landry S, Enchev RI, Sherker A, Munro M, Pinder J, Salsman J, Dellaire G, Xia B, Peter M, Durocher D.

3. Mitosis Inhibits DNA Double-Strand Break Repair to Guard Against Telomere Fusions. Science, 2014 Apr; 344(6180).
   Orthwein A, Fradet-Turcotte A, Noordermeer SM, Canny MD, Brun CM, Strecker J, Escribano-Diaz C, Durocher D.

4. Expression of the BRCA1 complex member BRE predicts disease free survival in breast cancer. Breast Cancer Research and Treatment, 2012 Aug;135(1).
   Noordermeer SM, Wennemers M, Bergevoet SM, Van der Heijden A, Tönnissen E, Sweep FCGJ, Jansen JH, Span PN, Van der Reijden BA.

5. High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9 positive patients. Blood, 2011 Nov;118(20).
   Noordermeer SM, Sanders MA, Gilissen C, Tönnissen E, Van der Heijden A, DöhnerK, Bullinger L, Jansen JH, Valk PJM, Van der Reijden BA.

Neefjes has been trained as a chemist and entered the fields of cell biology and immunology during his PhD and post-doc. He has combined these fields since. Jacques Neefjes has made many seminal contributions to the fields of immunology, infection diseases, cell biology and chemical biology. His research has centred around the cell biology of MHC class I and MHC class II associated antigen presentation. These pathways are critical in tumorimmunotherapy. Neefjes has unravelled many steps in these pathways including the definition of DRiPs, the definition of the MIIC, the molecular control of vesicle transport by motor proteins, the control of lysosomal transport by the ER and cholesterol and many other issues central in cell biology. Collectively, his work has uncovered many steps in the cell biology of antigen presentation by MHC class I and MHC class II molecules. His activities in the area of chemical immunology has yielded the first host targeting antibiotic targets and lead structures that support the host in bacterial clearance. This was the basis of his latest findings showing how Salmonella infections cause colon and gallbladder cancer. Combining epidemiology and lab experiments uncovered Salmonella as an environmental factor contributing to colon cancer risk and the identification of dangerous vs mild Salmonella isolates contributing to cancer.

As chairman of the Gravity program Chemical Immunology, Neefjes continued working on anthracyclines by combining chemistry with genetics and bioinformatics. This has yielded new discoveries on the action of an old drug. Neefjes has subsequently used this to synthesize away the cardiotoxic effects of these drugs without loss in anti-cancer activity. He is now making two detoxified variants for clinical testing, starting in 2023 and 2024.

• 2020 Spinoza Premium

• 2020: Ceppellini Award from the European Federation of Immunogeneticsts

• 2019: Josephine Nefkens Award for cancer research

• 2016: ERC Advanced Grant

• 2015: van Loghem Lecture, the annual career award for research in Immunology from the Dutch Immunology Society NVVI

• 2015: Elected member of the Dutch Royal Society of Sciences and Arts (KNAW)

• 2015: Elected member and Dutch representative in the EU COST Scientific Committee

• 2014: Elected member of the Norwegian Academy of Science and Letters (Det Norske Videnskaps-Akademi)

• 2013: Recipient and main applicant Gravity Program Institute for Chemical Immunology ICI

• 2013: Elected member Academia Europaea

• 2010: Elected member European Academy of Cancer Sciences

• 2009: ERC Advanced Grant

• 2007: Elected member EMBO

• 1996: Pioneer Grant

• 1996: Golden Medal of the Royal Dutch Chemical Society (KNCV)

• 1990: Antoni van Leeuwenhoek award

1. Jongsma, M. L., Berlin, I., Wijdeven, R. H., Janssen, L., Janssen, G. M., Garstka, M. A., ... & Neefjes, J. (2016). An ER-associated pathway defines endosomal architecture for controlled cargo transport. Cell, 166(1), 152-166.

2. Perrin P, Janssen L, Janssen H, van den Broek B, Voortman LM, van Elsland D, Berlin I, Neefjes J. (2021) Retrofusion of intralumenal MVB membranes parallels viral infection and coexists with exosome release. Curr Biol. 31(17):3884-3893

3. Pang, B., Qiao, X., Janssen, L., Velds, A., Groothuis, T., Kerkhoven, R., ... & Neefjes, J. (2013). Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nature Comm, 4, 1908.

4. Paul, P., van den Hoorn, T., Jongsma, M. L., Bakker, M. J., Hengeveld, R., Janssen, L., ... & Neefjes, J. (2011). A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell, 145(2), 268-283.

5. Scanu, T., Spaapen, R. M., Bakker, J. M., Pratap, C. B., Wu, L. E., Hofland, I., ... & Neefjes, J. (2015). Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Cell host & microbe, 17(6), 763-774.

Peter ten Dijke received his Ph.D. degree in 1991 from Wageningen University, The Netherlands based on his research on the identification of the third isoform of TGFβ performed at Oncogene Science, Inc., New York, USA. He did his postgraduate studies with Kohei Miyazono and Carl-Henrik Heldin at the Ludwig Institute for Cancer Research (LICR), Uppsala, Sweden. In 1994, he became group leader at LICR and moved in 1999 to the Netherlands Cancer Institute, Amsterdam, The Netherlands. In 2005, he became a professor of molecular cell biology at Leiden University Medical Center.

The overall aim of our work is to obtain a fundamental understanding on how cells communicate with each other, how this contributes to cancer progression when it goes awry ,and how we can manipulate it for therapeutic benefit. We use innovative integrated biological, genetic and chemical approaches to monitor and manipulate dynamic signal transduction processes. In particular, our research is focussed on elucidating the molecular mechanisms by which the multifunctional TGF-b family cytokines maintain tissue homeostasis and promote cancer progression.

Breakthrough discoveries were the identification and functional characterization of TGF-b family cell surface receptors and their downstream SMAD effector proteins. Moreover, we identified pivotal (druggable) regulators of TGF-b-induced epithelial of cancer cell plasticity and metastasis. Our research on how TGF-β controls tumor angiogenesis have led to new targeting agents that are being tested clinically. More recently, new insights were obtained into how ubiquitin modifications of TGF-β receptors and SMADs control their function and stability. The E3 ubiquitin ligases and deubiquitinating enzymes that were identified are novel targets for (immune) oncology drugs.

• 2022: Marshall R. Urist lecture Award

• 2021: Member of Academy of Europe

• 2018: Member of Royal Netherlands Academy of Arts and Sciences

• 2016: EMBO member

• 2015: Noreen Cunningham lecture award

• 2015: FEBS national lecture award

• 2015: Chang Jiang Scholar award from the Chinese Ministry of Education

• 2010: LUMC Education prize for best Frontiers in Science course for master students biomedical sciences

• 2006: VICI grant Netherlands Organization for Scientific Research

• 2005: Honorary Doctor of Medicine Uppsala University, Sweden

• 1998: Small Fernström prize for promising scientist in Sweden

• 1992-1993: Long-term EMBO Fellowship

1. Zhang J, van der Zon G, Ma J, Mei H, Cabukusta B, ... & Ten Dijke P. ST3GAL5 catalysed gangliosides inhibit TGF-β-induced epithelial-mesenchymal transition via TβRI degradation. EMBO J., in press.

2. Xie F, Zhou X, Li H, Su P, Liu S, ... & Ten Dijke P*, Zhou F*, Zhang L*. USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII. EMBO J. 2022 41:e108791. (*corresponding author)

3. Liu S, González-Prieto R, Zhang M, Geurink PP, Kooij R, ... & Ten Dijke P. Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-Induced breast cancer metastasis. Clin Cancer Res. 2020 26:1460-1473.

4. Zhang L, Zhou F, de Vinuesa A G, de Kruijf E M, Mesker W E, ... & Ten Dijke P (2013). TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. Molecular Cell, 51, 559-572.

5. Nakao A, Afrakhte M, Morn A, Nakayama T, Christian J L, ... & Ten Dijke P. (1997). Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature, 389, 631-635.

1. Z. Abdulrahman, S.J. Santegoets, G. Sturm, P. Charoentong, M.E. IJsselsteijn, A. Somarakis, T. Höllt, F. Finotello, Z. Trajanoski, S.L. van Egmond, D.A.M. Mustafa, M.J.P. Welters, N.F.C.C. de Miranda,S.H. van der Burg (2022) Chemokine-driven spatial organization of immune cell microaggregates marks oropharyngeal squamous cell carcinomas containing tumor-specific T cells. J. Immunother. Cancer, e004346

2. C.L. Duurland, S.J. Santegoets, Z. Abdulrahman, N.M. Loof, G. Sturm, T.H. Wesselink, R. Arens, S. Boekestijn, I. Ehsan, M.I.E. van Poelgeest, F. Finotello, H. Hackl, Z. Trajanoski, P. ten Dijke, V.M. Braud, M.J.P. Welters, S.H. van der Burg(2022) CD161 expression and regulation defines rapidly responding effector CD4+ T cells associated with improved survival in HPV16-associated tumors. J. Immunother. Cancer, 10:e003995

3. K.E. Kortekaas, S.J. Santegoets, L. Tas, I. Ehsan, P. Charoentong, H.C. van Doorn, M.I.E. van Poelgeest, D.A.M. Mustafa, S.H. van der Burg (2021) Primary vulvar squamous cell carcinomas with high T cell infiltration and active immune signaling are potential candidates for neoadjuvant PD1/PD-L1 immunotherapy. J. Immunother. Cancer, 9:e003671

4. E. Beyranvand Nejad, C. Labrie, M.J. van Elsas, J.W. Kleinovink, H.W. Mittrücker, K.L.M.C. Franken, S. Heink, T. Korn, R. Arens, T. van Hall, S.H. van der Burg (2021) IL-6 signalling in macrophages is required for immunotherapy-driven regression of tumors. J. Immunother. Cancer, 9:e002460

5. M. Saxena*, S.H. van der Burg*, C.J.M. Melief*, N. Bhardwaj* (2021) Therapeutic cancer vaccines. Nat Rev Cancer, 21:360-378

6. E. Beyranvand Nejad, C. Labrie, Z. Abdulrahman, M.J. van Elsas, E. Rademaker, J.W. Kleinovink, T.C. van der Sluis, S. van Duikeren, A.F.A.S. Teunisse, A.G. Jochemsen, J. Oosting, N.F.C.C de Miranda, T. van Hall, R. Arens, S.H. van der Burg (2020) Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy. J. Immunother. Cancer, 8: e001326

7. S.J. Santegoets, C.L. Duurland, E.S. Jordanova, J.J. van Ham, I. Ehsan, N.M. Loof, V. Narang, C.A. Dutertre, F. Ginhoux, S.L. van Egmond, M.J.P. Welters, S.H. van der Burg (2020)CD163⁺ cytokine-producing cDC2 stimulate intratumoral type 1 T cell responses in HPV16-induced oropharyngeal cancer. J. Immunother. Cancer, 8:e001053

8. K.E. Kortekaas, S.J. Santegoets, G. Sturm, I. Ehsan, S.I. van Egmond, F. Finotello, Z. Trajanoski, M.J.P. Welters, M.I.E. van Poelgeest, S.H. van der Burg (2020) CD39 identifies the CD4-positive tumor-specific T cell population in human cancer. Cancer Immunol. Res., 8: 1311-1321

9. E.M.E. Verdegaal^*, M.K. van der Kooij^*, M. Visser, C.E. van der Minne, L. de Bruin, P.M. Meij, A.G.T. Terwisscha van Scheltinga, M.J.P. Welters, S.J.A.M. Santegoets, N.F.C.C. de Miranda C.F.M. Roozen, G.J. Liefers, E. Kapiteijn^**, S.H. van der Burg^** (2020) Low-dose Interferon-alpha pre-conditioning and adoptive cell therapy in metastatic melanoma patients refractory to standard (immune) therapies – a phase 1/2 study. J. Immunother. Cancer, 8: e000166

10. C.J.M. Melief*, M.J.P. Welters*, I. Vergote, J.R. Kroep, G.G. Kenter, P.B. Ottevanger, W.A.A. Tjalma, H. Denys, M.I.E. van Poelgeest, H.W. Nijman, A.K.L. Reyners, T. Velu, F. Goffin, R.I. Lalisang, N.M. Loof, S. Boekestijn, W.J. Krebber, L. Hooftman, S.Visscher, B.A. Blumenstein, R.B. Stead, W. Gerritsen**, S.H. van der Burg** (2020) Strong vaccine responses during chemotherapy are associated with prolonged cancer survival. Science Translational Medicine, 12 (535): eaaz8235

11. Z. Abdulrahman, N.F.C.C. de Miranda, E.M.G. van Esch, P.J. de Vos van Steenwijk, H.W. Nijman, M.J.P. Welters, M.I.E. van Poelgeest^*, S.H. van der Burg^* (2020) Pre-existing inflammatory immune microenvironment predicts the clinical response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 vaccination. J. Immunother. Cancer, 8(1): e000653

12. N. Hilf, S. Kuttruff-Coqui, K. Frenzel, V. Bukur, S. Stevanovic, C. Gouttefangeas, M. Platten, G. Tabatabai, V. Dutoit, S.H. van der Burg, P. thor Straten, F. Martinez Ricarte, B. Ponsati, H. Okada, U. Lassen, A. Admon, C.H. Ottensmeier, A. Ulges, S. Kreiter, A. von Deimling, M. Skardelly, D. Migliorini, J.R. Kroep, M. Idorn, J. Rodon, J. Piro, H.S. Poulsen, B. Shraibman, K. McCann, R. Mendrzyk, M. Löwer, M. Stieglbauer, C. Britten, D. Capper, M.J.P. Welters, J. Sahuquillo, K. Kiesel, E. Derhovanessian, E. Rusch, C. Song, S. Heesch, C. Wagner, A. Kemmer-Brueck, J. Ludwig, J.C. Castle, O. Schoor, A. Tadmor, J. Fritsche, M. Meyer, N. Pawlowski, S. Dorner, F. Hoffgaard, B. Rössler, D. Maurer, T. Weinschenk, C. Reinhardt, C. Huber, H.G. Rammensee, H. Singh, U. Sahin, P.Y. Dietrich, W. Wick (2019) Actively personalized vaccination in newly diagnosed glioblastoma. Nature, 565:240-245

13. E.M.E. Verdegaal, N.F. de Miranda, M. Visser, T. Harryvan, M.M. van Buuren, R.S. Andersen, S.R. Hadrup, C.E. van der Minne, R. Schotte, H. Spits, J.B.A.G. Haanen, E.H.W. Kapiteijn, T.N. Schumacher, S.H. van der Burg (2016) Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature, 526:91-95

14. M.J. Welters*, T.C. van der Sluis*, H. van Meir*, N.M. Loof, H.J. van Ham, S. van Duikeren, S.J. Santegoets, R. Arens, M.L. de Kam, A.F. Cohen, M.I.E. van Poelgeest, G.G. Kenter, J.R. Kroep, K. Burggraaf, C.J.M. Melief, S.H. van der Burg (2016) Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T-cell responses. Science Translational Med., 8:334ra52

15. C. Linnemann, M.M. van Buuren, L. Bies, E.M. Verdegaal, R. Schotte, J.J.A. Calis, S. Behjati, A. Velds, H. Hilkmann, D. el Atmioui, M. Visser, M.R. Stratton, J.B.A.G. Haanen, H. Spits, S.H. van der Burgand T.N.M. Schumacher (2015) Intratumoral CD4⁺ T cell reactivity against mutated antigens is commonly observed in human melanoma. Nature Med., 21:81-85