Prekovic Lab at UMC Utrecht
Chromatin-related factors and lineage plasticity
Computational Oncogenomics
News
12/02/2024
Masa Milutinovic has joined our lab for her master degree internship. Welcome Masa!
08/02/2024
We have been recognized by the Dutch Endocrine Society with the āfundamental article of the yearā award for our paper focused on the role of glucocorticoids in luminal breast cancer.
15/12/2023
Stefan has authored a Viewpoint commissioned by Nature Cancer, which underscores the challenges inherent in launching a research group.
26/11/2023
Tessa Mulder has joined our lab for her master degree internship. Welcome Tessa!
01/11/2023
We are happy to welcome Julia Scott as a new member of our team. Julia will work as a postdoc on KWF funded project focused on inspecting the role of STAG2 on lineage plasticity in lung cancer.
30/10/2023
Our latest study, published in Embo Molecular Medicine, highlights the glucocorticoid receptor's (GR) key role in primary cancer biology, especially in determining ER-positive breast cancer subtypes and patient outcomes.
26/10/2023
Danae Welboren has joined our lab for her master degree internship. Welcome Danae!
For older news see News Archive.
Research
Transcription factors have for years been considered attractive targets in cancer therapeutic development. Emergence of specific drugs for targeting these proteins led to optimized use in cancer treatment, with many of these drugs becoming part of standard-of-care regiments. The nuclear receptor family of transcription factors is of particular interest, as their pharmacological targeting leads to growth suppression in both solid and liquid cancers. This is best exemplified in breast and prostate cancer, for which inhibitors of Estrogen and Androgen receptors are used to stop cancer growth/progression, and lymphoid cancers where activators of the Glucocorticoid receptors induce apoptosis. While targeting nuclear receptors is initially effective, all cancers will eventually adapt and become resistant to these therapies through various mechanisms that most often include re-activation of nuclear receptor signalling through various means. Therefore, target discovery, drug development and pre-clinical testing remain a constant clinically unmet need.
Glucocorticoid Receptor in Cancer
Glucocorticoids, a class of steroid hormones, have a complex relationship with cancer. While they can suppress the immune system and promote cancer growth, they can also induce apoptosis and inhibit cancer cell proliferation. The glucocorticoid receptor (GR) plays a key role in mediating these effects, and targeting the GR pathway may be a promising strategy for treating certain types of cancer. However, further research is needed to fully understand the role of glucocorticoids in cancer and to develop effective therapies that can exploit their anti-cancer effects.
Projects related to the glucocorticoid receptor in lung and breast cancer are supported by funding from the Dutch Cancer Foundation (KWF) and are done in collaboration with Zwart lab, Netherlands Cancer Institute.
STAG2, transcription factors and lineage determination
Lung cancer is deadly, with 83% of patients dying within 5 years of diagnosis. STAG2 loss in 20% of cases leads to poor survival and a mucinous cell-like state. Our research shows altered growth patterns and metabolic changes in STAG2-deficient lung cancer cells, with vulnerabilities to PARP and BRD inhibitors. We aim to study lineage maintenance in STAG2-deficient lung cancer and test the effectiveness of these inhibitors in pre-clinical models, with the goal of developing better therapies and diagnostics to improve patient outcomes. Hear more about this research line in Stefanās research pitch here.
Projects related to the STAG2 function in lung cancer are funded by Alpe/dāHuiz and Bus Mulder Award.
Locus-specific regulation by transcription factors
Our research focuses on unraveling the mystery of how steroid hormone receptors (SHRs) regulate transcriptional activity. We use FACS-based genome-wide CRISPR screening to investigate the essential components of the SHR-recruited co-regulator complex that drive transcription following hormonal stimuli. Our findings reveal a functional cross-talk between PAXIP1 and STAG2, which are critical co-regulators of the Glucocorticoid Receptor (GR) complex. We demonstrate that PAXIP1 and STAG2 are required to maintain 3D-genome architecture and drive the GR transcriptional programme following hormonal stimuli. In lung cancer, PAXIP1/STAG2 loss enhances GR-mediated tumor suppressor activity by modifying local chromatin interactions. Overall, our research introduces PAXIP1 and STAG2 as novel co-regulators of GR, opening up new avenues for understanding transcriptional regulation in hormonal signaling (Mayayo-Peralta et al, 2023, NAR).
Publications
Recent publications
Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity.
Prekovic S, Chalkiadakis T*, Roest M*, Roden D, Lutz C, Schuurman K, Opdam M, Hoekman L, Abbott N, Tesselaar T, Wajahat M, Dwyer AR, Mayayo-Peralta I, Gomez G, Altelaar M, Beijersbergen R, GyÅrffy B, Young L, Linn S, Jonkers J, Tilley W, Hickey T, Vareslija D, Swarbrick A, Zwart W.
*denotes shared first authorship
Proteomics on malignant pleural effusions reveals ERĪ± loss in metastatic breast cancer associates with SGK1-NDRG1 deregulation
Mayayo-Peralta I, Debets DO, Prekovic S, Schuurman K, Beerthuijzen S, Almekinders M, Sanders J, Moelans CB, Saleiro S, Wesseling J, van Diest PJ, Henrique R, JerĆ³nimo C, Altelaar M, Zwart W. Mol Oncol. 2023 Oct 19. doi: 10.1002/1878-0261.13540. Online ahead of print.
Clarisse D, Prekovic S, Vlummens P, Staessens E, Van Wesemael K, Thommis J, Fijalkowska D, Acke G, Zwart W, Beck IM, Offner F, De Bosscher K. Cell Mol Life Sci. 2023 Aug 14;80(9):249. doi: 10.1007/s00018-023-04900-x.
Perturbations in 3D genome organization can promote acquired drug resistance.
ManjĆ³n AG, Manzo SG, Prekovic S, Potgeter L, van Schaik T, Liu NQ, Flach K, Peric-Hupkes D, Joosten S, Teunissen H, Friskes A, Ilic M, Hintzen D, Franceschini-Santos VH, Zwart W, de Wit E, van Steensel B, Medema RH. Cell Rep. 2023 Oct 31;42(10):113124. doi: 10.1016/j.celrep.2023.113124. Epub 2023 Sep 20.
Inhibiting the Glucocorticoid Receptor to Enhance Chemotherapy Response.
Prekovic S#, Zwart W. J Clin Oncol. 2023 Oct 20;41(30):4790-4793. doi: 10.1200/JCO.23.01195. Epub 2023 Aug 3.
#denotes corresponding authorship
PAXIP1 and STAG2 converge to maintain 3D genome architecture and facilitate promoter/enhancer contacts to enable stress hormone-dependent transcription
Mayayo-Peralta I, Gregoricchio S, Schuurman K, Yavuz S, Zaalberg A, Kojic A, Abbott N, Geverts B, Beerthuijzen S, Siefert J, Severson TM, van Baalen M, Hoekman L, Lieftink C, Altelaar M, Beijersbergen RL, Houtsmuller AB, Prekovic S#, Zwart W#. Nucleic Acids Res. 2023 Apr 18:gkad267. doi: 10.1093/nar/gkad267.
#denotes co-corresponding authorship
Mammalian life depends on two distinct pathways of DNA damage tolerance
Buoninfante OA*, Spanjaard A*, Pilzecker B*, de Groot D*, Prekovic S$, Song JY, Lieftink C, Ayidah M, Huijbers IJ, Pritchard CEJ, ViviƩ J, Philipsen S, Pallis J, Zwart W, Beijersbergen R, van den Berk PCM, Jacobs H. Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2216055120. doi: 10.1073/pnas.2216055120. Epub 2023 Jan 20.
*denotes shared first authorship / $denotes second authorship
Racine F, Louandre C, Godin C, Chatelain B, Prekovic S, Zwart W, Galmiche A, Saidak Z. Cancers (Basel). 2023 Feb 28;15(5):1531. doi: 10.3390/cancers15051531.
Ribosome impairment regulates intestinal stem cell identity via ZAKÉ activation.
Silva J, Alkan F, Ramalho S, Snieckute G, Prekovic S, Garcia AK, HernƔndez-PƩrez S, van der Kammen R, Barnum D, Hoekman L, Altelaar M, Zwart W, Suijkerbuijk SJE, Bekker-Jensen S, Faller WJ Nat Commun. 2022 Aug 2;13(1):4492. doi: 10.1038/s41467-022-32220-4.
Team
Group photo
Assistant professor / Group leader
Postdoc: Computational biology/Omics, Netherlands Cancer Institute, Netherlands
PhD: Biochemistry/Bioinformatics, KU Leuven, Belgium
BSc/MSc: Molecular Genetics, University of Belgrade, Serbia
Stefan Prekovic
Born and raised in a quaint Serbian town, I earned my BSc/MSc degrees from the University of Belgrade before relocating to Belgium. There, I joined Frank Claessens' lab, exploring the androgen receptor's role in diverse diseases. Later, as a postdoctoral researcher at the Netherlands Cancer Institute, I worked with Wilbert Zwart on investigating transcription factor action in various cancer types using omics, screening, and computational methodologies.
PhD student
Theo Chalkiadakis
Born in Heraklion, Crete, Theofilos Chalkiadakis. began his academic journey at the University of Crete, earning a BSc in Biology. He then pursued an MSc in Bioinformatics from the joint program of Universiteit van Amsterdam and Vrije Universiteit Amsterdam in the Netherlands. Currently, Theofilos is focusing on utilizing computational strategies to unravel the complex actions of transcription factors, further advancing our understanding of their roles and impacts.
MSc: Bioinformatics, Universiteit van Amsterdam/Vrije Universiteit Amsterdam, Netherlands
BSc: Biology, University of Crete, Greece
Born in Thessaloniki, Greece, Emmanouela Epeslidou recently completed her undergraduate MSci Biology studies at the University of Ioannina, where she majored in Biomolecular Sciences and Biotechnology. Emmanouela has amassed valuable research experience through internships at prestigious institutions like the Netherlands Cancer Institute and AHEPA General University Hospital. Her undergraduate thesis focused on investigating the potential anticancer activity of Pimozide in lung cancer mouse models.
Research Assistant
BSc/MSc: Biological Applications and Technology, University of Ioannina, Greece
Emma Epeslidou
Senior Research Assistant
BSc/MSc: Life Sciences (Microbiology), Hogeschool Utrecht
Mehmet Yilmaz
Mehmet Started his career at the Hubrecht Institute in Utrecht, where he worked on developing a proximity ligation technology. He then joined the startup company Cergentis where he helped develop the technology for commercial purposes. With a strong background in R&D, he has worked as a Senior Product Developer at Cergentis since 2012. Mehmet's expertise spans molecular genetic techniques, targeted enrichment strategies and NGS sequencing.
Postdoctoral Fellow
PhD: Medicine, University of Adelaide, Adelaide, Australia
MSc: Medical Science, Flinders University, Adelaide, Australia
BSc: Biology, University of Adelaide, Adelaide, Australia
Julia Scott
Julia comes from Adelaide, Australia, where she earned her BSc (Advanced) degree in biochemistry and chemistry from The University of Adelaide, before undertaking an MSc (Honours) research year at Flinders University. She completed her doctoral training at The University of Adelaide, under the guidance of Prof. Lisa Butler, studying the role of lipid metabolism in prostate cancer progression.
Master Student
MSc: CSND, UMC Utrecht, Utrecht, The Netherlands
BSc: University of Amsterdam, Amsterdam, The Netherlands
Danae Welboren
Masa Milutinovic
Master Student
MSc: University of Groningen, Groningen, The Netherlands
BSc: University of Groningen, Groningen, The Netherlands
My name is Masa Milutinovic, I am Serbian but have lived in The United Arab Emirates for most of my life. I have completed my bachelor studies at the University of Groningen in Biology in 2022 and am currently a master student studying biomedical sciences. My interests lie in cancer and immunology and the interplay between the two. I am joining the Prekovic lab at the UMC Utrecht to pursue an internship and expand my bioinformatics skillset.
Merel Roest
PhD student (promotor: prof Wilbert Zwart; based at the NKI, Amsterdam)
MSc: Biology, Univeristy of Utrecht, Utrecht, Netherlands
BSc: Biology, Univeristy of Utrecht, Utrecht, Netherlands
Master Student
MSc: CSND, UMC Utrecht, Utrecht, The Netherlands
BSc: University of Utrecht, Utrecht The Netherlands
Tessa Mulder
Isabel Mayayo-Peralta, PhD student (co-supervised by prof. Wilbert Zwart (promotor); based at the NKI)
Nina Abbott, master student (project writing)
Loubna Ayadi, master student (literature review thesis)