X. Bisteau

Mass Spectrometry and Proteomics platformControl of cell proliferation ; cancer
Written By Aleks

Our research

The vulnerability of cancer cells to their addiction to kinase activities

In decades, the survival rate of several cancers has barely been improved. The survival and the proliferation of such cancers strongly rely on a network of kinases of which the activities fluctuate. Every tumors harbor a variety of genetic alterations directly or indirectly affecting the activity of kinases involved in signaling pathways, the cell cycle or the proliferation. However, the heterogeneity of alterations in such tumors has rendered difficult the development of a unique therapeutic strategy to treat a unique cancer type. It is therefore essential to evaluate how tumors are addicted to kinases and their activities parallel to specific oncogenic alterations.

Our research focuses on assessing the addiction of cancer cells to kinase activities and predict their response to kinases inhibitors using a multiomics approach. At this end, our lab takes advantage of various in vitro and in vivo models especially of oesophageal squamous carcinoma to challenge tumor cells to their kinase addiction.

As the CDK4 activity lies downstream from most of the oncogenic deregulations of signalling pathways, it has been proposed to represent the therapeutic target of choice. Despite this, not all tumors respond to CDK4 inhibition and long-term treatment triggers escape mechanisms. In this context, it is crucial to characterize the sensitivity of tumors including eSCC to CDK4 inhibition, understand the CDK4 inhibition on the cell cycle progression and chromosome instability to fully decipher the molecular response for effective combined targeted therapy.

We try to address all these questions using various approaches combining:

  • Mass spectrometry based proteomics and phosphoproteomics

  • Bidimensional electrophoresis and kinase assays

  • NGS and bioinformatics

  • Transgenic mouse models

  • 2D/3D cell cultures of cancer cell lines/isolated mouse tumor/patient tumor derived cells

  • Immunofluorescence and time lapse imaging

Funded by MSCA action and Innoviris Brain 2 Brussels – Attract program

Group Members

Xavier Bisteau, PhD


Group leader (Xavier.Bisteau@ulb.ac.be)

Dr Xavier Bisteau is an Assistant Professor of molecular and cell biology among the faculty of medicine at the Université Libre de Bruxelles (ULB) and a research group leader at the IRIBHM J.E. Dumont. He graduated as a molecular biologist (MS in 2007) and earned his PhD in biomedical and pharmaceutical sciences from the Université Libre de Bruxelles (ULB) in 2013. He performed a postdoctoral training at IMCB (A*STAR) in Singapore from 2013 to 2019. He was awarded major fundings (Marie Curie fellowship and Innoviris – Attract) to return as independent research fellow at ULB in 2019 and officially started his lab in 2021. His lab research focusses on the addiction of cancer to kinase activities, especially CDK4/6 and their responses to pharmacological inhibition, their interplay with microenvironment and the molecular mechanisms of intrinsic and acquired resistance. Besides his lab research, Pr. Bisteau is managing a growing core facility of Mass Spectrometry for proteomics analysis to assess protein abundances and post-translational modifications with numerous collaborators for various diseases as multiples sclerosis, Alzheimer, epilepsy both on experimental lab, patients’ samples as well as plants and other animals’ samples. Parallel to his teaching activities, Pr. Bisteau is pioneering pedagogical concepts, especially using numeric modules and systems including virtual reality as a tool for students to better learn and simulate environments and practical procedures.

Virginie Imbault, MS

Virginie received her master in genetics and microbiology in 2004 and a professional master in proteomics in 2005 from the University of Lille 1. She joined the institute in 2006 and is the technical manager of the proteomics facility. She is working in collaboration with our group, the group of David Communi and all collaborators interested in MS-based proteomics analyses.

Fabiana Moresi, PhD student

Fabiana Moresi is a Ph.D. candidate in Biomedical Science at the Université libre de Bruxelles (ULB), working in the laboratory of Prof. Xavier Bisteau. Her research investigates the heterogeneous and dynamic response of esophageal squamous cell carcinoma (eSCC) to CDK4/6 inhibition, using both 2D and 3D in vitro models. Fabiana earned her MSc with honors in Genetics and Molecular Biology from La Sapienza University of Rome and completed a double-degree program at the Magistère Européen de Génétique in Paris. Passionate about translational research and tumor modeling, she is currently collaborating with Dr. Andrea Pavesi at A*STAR, where she is exploring microfluidic-based platforms to recapitulate the tumor–immune microenvironment. Her work bridges molecular biology, cancer therapeutics, and bioengineering. Recipient of several awards—including the EMBO Scientific Exchange Grant and the FRIA doctoral fellowship—Fabiana actively mentors graduate students and contributes to international conferences. She is committed to advancing preclinical cancer models to better understand therapy resistance and immunomodulation.

Marta Avalo, PhD student

Marta received her master degree in 2020 from the University of Granada. She further studied bioinformatics at the KU Leuven before joining the lab in November 2021. Marta is studying the dynamic changes of the protein-protein interaction network parallel to phosphorylation modulations following kinase inhibition in cancer.

Diego Japón Ruiz, PhD Student

…

Publications

26        Bande M, Delporte C, Sakira AK, Bourez A, Imbault V, Bisteau X, Sombie C, Some TI, Antwerpen PV. Development of an analytical model for assessing the adsorptive properties of traditional medicinal formulations from Burkina Faso in relation to snake venom proteins. doi: 10.1016/j.toxicon.2025.108470

25        Kaafarani A, Darche-Gabinaud R, Bisteau X, Imbault V, Wittamer V, Parmentier M, Pirson I. Proximity Interactome Analysis of Super Conserved Receptors Expressed in the Brain Identifies EPB41L2, SLC3A2, and LRBA as Main Partners. doi: 10.3390/cells12222625

24        Sabine Paternot, Eric Raspé, Clément Meiller, Maxime Tarabichi, Jean-Baptiste Assié, Frederick Libert, Myriam Remmelink, Xavier Bisteau, Patrick Pauwels, Yuna Blum, Nolwenn Le Stang, Séverine Tabone-Eglinger, Françoise Galateau-Sallé, Christophe Blanquart, Jan P Van Meerbeeck, Thierry Berghmans, Didier Jean, Pierre P Roger. Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition. doi: 10.1002/1878-0261.13351

23        Mireia Rovira, Magali Miserocchi, Alice Montanari, Latifa Hammou, Laura Chomette, Jennifer Pozo, Virginie Imbault, Xavier Bisteau, Valérie Wittamer. (2022). Zebrafish Galectin 3 binding protein is the target antigen of the microglial 4C4 monoclonal antibody. doi: 10.1002/dvdy.549

22        Redondo Marin, J. A., Bibes, R., Vercauteren Drubbel, A., Dassy, B., Bisteau, X., Maury, E., & Beck, B. (2021). PER2 Circadian Oscillation Sensitizes Esophageal Cancer Cells to Chemotherapy. Biology, 10(4), 266. doi:10.3390/biology10040266

21        Dewhurst MR, Ow JR, Zafer G, van Hul NKM, Wollmann H, Bisteau X, Brough D, Choi H, Kaldis P. (2020) Loss of hepatocyte cell division leads to liver inflammation and fibrosis. PLoS Genet. 16(11):e1009084. doi: 10.1371/journal.pgen.1009084.

20        Bisteau X*, Lee J, Srinivas V, Lee JHS, Niska-Blakie J, Tan G, Yap SYX, Hom KW, Wong CK, Chae J, Wang LC, Kim J, Rancati G, Sobota RM, Tan CSH, Kaldis P. (2020) The Greatwall kinase safeguards the genome integrity by affecting the kinome activity in mitosis. Oncogene. (44):6816-6840. doi: 10.1038/s41388-020-01470-1 *corresponding author

19        Palmer N, Talib SZA, Ratnacaram CK, Low D, Bisteau X, Lee JHS, Pfeiffenberger E, Wollmann H, Tan JHL, Wee S, Sobota R, Gunaratne J, Messerschmidt DM, Guccione E, Kaldis P. (2019) CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I. J Cell Biol. 218(9):2896-2918. doi: 10.1083/jcb.201903125.

18        Szmyd R., Niska-Blakie J., Diril M.K., Renck Nunes P., Tzelepis K., Lacroix A., van Hul N., Deng LW., Matos J., Dreesen O., Bisteau X., Kaldis P. (2018) Premature activation of Cdk1 leads to mitotic events in S phase and embryonic lethality Oncogene. 2019 Feb;38(7):998-1018. doi: 10.1038/s41388-018-0464-0

17        Dai L., Zhao T., Bisteau X., Sun W., Prabhu N., Lim YT., Sobota R., Kaldis P., Nordlund P. (2018) Modulation of protein interaction states through the cell cycle. Cell 173(6):1481-1494.e13 doi: 10.1016/j.cell.2018.03.065

16        Tan CSH., Go KD., Bisteau X., Dai L., Yong CH., Prabhu N., Ozturk MB., Lim YT., Sreekumar L., Lengqvist J., Tergaonkar V., Kaldis P., Sobota S., Nordlund P. (2018) Thermal Proximity Co-aggregation for System-wide Monitoring of Protein Complex Dynamics in Intact Cell. Science  359(6380):1170-1177 doi: 10.1126/science.aan0346

15        Windpassinger, C., Piard, J., Bonnard, C., Alfadhel, M., Lim, S., Bisteau, X., et al. (2017). CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. American Journal of Human Genetics, 101(3), 391–403

14        Colleoni, B., Paternot, S., Pita, J. M., Bisteau, X., Coulonval, K., Davis, R. J., et al. (2017). JNKs function as CDK4-activating kinases by phosphorylating CDK4 and p21. Oncogene, 9, 391. http://doi.org/10.1038/onc.2017.7

13        Kim, S. Y., Lee, J.-H., Merrins, M. J., Gavrilova, O., Bisteau, X., Kaldis, P., et al. (2017). Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary β-Cell Dysfunction to Progressive Depletion of β-Cell Mass and Diabetes. The Journal of Biological Chemistry, 292(9), 3841–3853. http://doi.org/10.1074/jbc.M116.754077

12        Jayapal, S. R., Ang, H. Y.-K., Wang, C. Q., Bisteau, X., Caldez, M. J., Xuan, G. X., et al. (2016).  Cyclin A2 regulates erythrocyte morphology and numbers. Cell Cycle (Georgetown, Tex.), 1–12. http://doi.org/10.1080/15384101.2016.1234546

11        Chauhan, S., Diril, M. K., Lee, J. H. S., Bisteau, X., Manoharan, V., Adhikari, D., et al. (2016). Cdk2 catalytic activity is essential for meiotic cell division in vivo. The Biochemical Journal, 473(18), 2783–2798. http://doi.org/10.1042/BCJ20160607

10        Diril, M. K*., Bisteau, X.*, Kitagawa, M., Caldez, M. J., Wee, S., Gunaratne, J., et al. (2016). Loss of the Greatwall Kinase Weakens the Spindle Assembly Checkpoint. PLoS Genetics, 12(9), e1006310. http://doi.org/10.1371/journal.pgen.1006310.s015   * Co-first author

9          Heijink, A. M., Blomen, V. A., Bisteau, X., Degener, F., Matsushita, F. Y., Kaldis, P., et al. (2015). A haploid genetic screen identifies the G1/Sregulatory machinery as a determinant ofWee1 inhibitor sensitivity. Proceedings of the National Academy of Sciences of the United States of America, 201505283. http://doi.org/10.1073/pnas.1505283112

8          Jayapal, S. R., Wang, C. Q., Bisteau, X., Caldez, M. J., Lim, S., Tergaonkar, V., et al. (2015). Hematopoiesis specific loss of Cdk2 and Cdk4 results in increased erythrocyte size and delayed platelet recovery following stress. Haematologica, 100(4), 431–438. http://doi.org/10.3324/haematol.2014.106468

7          Bisteau, X., & Kaldis, P. (2014). Spy1/SpeedyA accelerates neuroblastoma. Oncotarget, 5(16), 6554–6555.

6          Bisteau, X., Caldez, M. J., & Kaldis, P. (2014). The Complex Relationship between Liver Cancer and the Cell Cycle: A Story of Multiple Regulations. Cancers, 6(1), 79–111. http://doi.org/10.3390/cancers6010079

5          Paternot, S., Colleoni, B., Bisteau, X., & Roger, P. P. (2014). The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes. Cell Cycle (Georgetown, Tex.). http://doi.org/10.4161/15384101.2014.946841

4          Farhang Ghahremani, M., Goossens, S., Nittner, D., Bisteau, X., Bartunkova, S., Zwolinska, A., et al. (2013). p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathway. Cell Death and Differentiation, 20(7), 888–897. http://doi.org/10.1038/cdd.2013.12

3          Bisteau, X.*, Paternot, S.*, Colleoni, B., Ecker, K., Coulonval, K., De Groote, P., et al. (2013). CDK4 T172 phosphorylation is central in a CDK7-dependent bidirectional CDK4/CDK2 interplay mediated by p21 phosphorylation at the restriction point. PLoS Genetics, 9(5), e1003546. http://doi.org/10.1371/journal.pgen.1003546.s011 * equal contribution

2          Paternot, S., Bockstaele, L., Bisteau, X., Kooken, H., Coulonval, K., & Roger, P. P. (2010). Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase. Cell Cycle (Georgetown, Tex.), 9(4), 689–699.

1          Bockstaele, L*., Bisteau, X.*, Paternot, S., & Roger, P. P. (2009). Differential regulation of cyclin-dependent kinase 4 (CDK4) and CDK6, evidence that CDK4 might not be activated by CDK7, and design of a CDK6 activating mutation. Molecular and Cellular Biology, 29(15), 4188–4200. http://doi.org/10.1128/MCB.01823-08  * Co-first author

Aleks
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