Xavier Bisteau

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

Group members

Xavier Bisteau, PhD,
Group leader (Xavier.Bisteau@ulb.ac.be)
phone # +32 2 555 4153

MSCA & Innoviris independent fellow – “Vulnerability of esophageal cancer to their addiction to kinase activities: evaluation and prediction of eSCC tumors responsiveness to kinase inhibitors”

2013-2019 – Postdoctoral fellow at the Cell Division and Cancer research Lab in the IMCB (A*STAR Singapore) under the supervision of Prof. Philipp Kaldis

2013 – PhD in Biomedical and pharmaceutical sciences (ULB, Brussels, Belgium) under the supervision of Dr Pierre Roger

Fabiana Moresi, PhD student
(Fabiana.Moresi@ulb.be)
phone +32 2 555 4164

2020 – Master degree in Genetics & Molecular Biology (La Sapienza, Roma, Italy & Paris-Diderot, Paris, France)

 

 

 

 

 

Publications

                 

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