Nuclear signaling and cancer (Dr Katia Zanier)

Summary

Research interests

Dr Katia Zanier

The research activities of the team can be grouped into two main and complementary axes, which address both fundamental and clinical aspects of Cancer Biology.

Research axis 1 (PI K. Zanier) deals with the characterization of protein-protein interaction mechanisms promoting oncogenesis in a wide variety of cancers. To this end, we combine proteomics analyses with structural, biochemical and functional approaches. Our current projects focus on two signaling pathways with major impact on cancer initiation and maintenance, namely the tumor suppressor p53 and NF-kBpathways. Using a cellular model system based on human papillomavirus (HPV) mediated transformation, we have identified novel interactors of p53 and of oncogenic isoforms of the p53 family of proteins and we are currently studying the role played by such interactions in both viral and non-viral induced oncogenesis. Another project deals with the mechanisms used by the IKK kinase, a central regulator of NF-kB signaling, to recognize its substrates. Here, our approach strategy relies on the identification and characterization of Small Linear Motifs (SLiMs) that mediate substrate docking to the catalytic core of the kinase.

Research axis 2 (PI L. Vallat) focuses on the leukemogenesis of leukemias and lymphomas developed from mature B lymphocytes. In particular, we are studying the role of lymphocyte response abnormalities following activation of the antigen receptor and of the downstream signaling pathways (including NF-kB) in the initiation of tumor proliferation. We are also investigating the role of this lymphocyte response in the emergence of clonal heterogeneity in the leukemic cell population. To this end, we have developed ex vivo 3D lymphocyte culture models reproducing the proleukemogenic conditions encountered in patients' lymphoid tissues. These models enable us to reconstruct the transcriptional and proteomic dynamics at the origin of tumor proliferation. Further development of such models also enables us to understand the sub-clonal lymphocyte response and the clonal heterogeneity. As part of a collaborative project with INRIA, we develop mathematical models of clonal heterogeneity to better predict the evolution of leukemia and the emergence of therapeutic resistance.

The ultimate goal of the team is to translate our findings into innovative therapeutic strategies. To this end, in parallel to the fundamental studies, we also run projects aiming at improving the delivery of peptides and/or RNAs targeting the mechanisms identified in our studies.

Funding

Team members

Publications

Li C, Moro S, Shostak K, O'Reilly FJ, Donzeau M, Graziadei A, McEwen AG, Desplancq D, Poussin-Courmontagne P, Bachelart T, Fiskin M, Berrodier N, Pichard S, Brillet K, Orfanoudakis G, Poterszman A, Torbeev V, Rappsilber J, Davey NE, Chariot A, Zanier K (2024). Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates. Nat Commun 15(1):7692. doi: 10.1038/s41467-024-52076-0.

Nisco A, Tolomeo M, Scalise M, Zanier K, Barile M (2024). Exploring the impact of flavin homeostasis on cancer cell metabolism. Biochim Biophys Acta Rev Cancer 1879(5):189149. doi: 10.1016/j.bbcan.2024.189149.

Loubaton R, Champagnat N, Vallois P, Vallat L (2024). MultiRNAflow: integrated analysis of temporal RNA-seq data with multiple biological conditions. Bioinformatics 40(5):btae315. doi: 10.1093/bioinformatics/btae315.

Ghergus D, Martin M, Knapp AM, Delmotte F, Joublin-Delavat A, Jung S, Schickel JN, Mendel I, Dupuis A, Drénou B, Ghesquières H, Salles G, Baseggio L, Herbrecht R, Korganow AS, Vallat L, Soulas-Sprauel P, Meffre E, Martin T (2024). Normal B cells express ZAP70 in chronic lymphocytic leukemia: A link between autoimmunity and lymphoproliferation? Am J Hematol99(1):48-56. doi: 10.1002/ajh.27137.

Taverniti V, Krynska H, Venuti A, Straub ML, Sirand C, Lohmann E, Romero-Medina MC, Moro S, Robitaille A, Negroni L, Martinez-Zapien D, Masson M, Tommasino M, Zanier K (2023). The E2F4/p130 Repressor Complex Cooperates with Oncogenic ΔNp73α To Inhibit Gene Expression in Human Papillomavirus 38 E6/E7-Transformed Keratinocytes and in Cancer Cells. mSphere 8(2):e0005623. doi: 10.1128/msphere.00056-23.

Mayeur S, Molitor A, Miguet L, Rigolot L, Naegely L, Stemmelen T, Meyer S, Toussaint E, Vallat L, Eischen A, Chenard MP, Tavian M, Bahram S, Carapito R, Nicolae A (2023). Multiomics of three hematological malignancies in a patient reveal their origin from clonal hematopoietic stem cells. Blood Cancer J13(1):118. doi: 10.1038/s41408-023-00892-w.

Duret PM, Schleiss C, Kawka L, Meyer N, Ye T, Saraux A, Devauchelle-Pensec V, Seror R, Larroche C, Perdriger A, Sibilia J, Vallat L, Fornecker LM, Nocturne G, Mariette X, Gottenberg JE (2023). Bruton’s tyrosine kinase (BTK) gene overexpression is associated with the risk of lymphoma in primary Sjögren’s syndrome. Arthritis Rheumatol 75(10):1798-1811. doi: 10.1002/art.42550.

Fournier E, Heiblig M, Lespinasse C, Flandrin-Gresta P, Geay A, Miguet L, Fenwarth L, Vallat L, Soubeyrand B, Marceau-Renaut A, Plesa A, Preudhomme C, Sujobert P, Hayette S, Duployez N, Huet S (2022). Molecular heterogeneity and measurable residual disease of rare NPM1 mutations in acute myeloid leukemia: a nationwide experience from the GBMHM study group. Leukemia 36(5):1390-1400. doi: 10.1038/s41375-022-01534-z.

Schleiss C, Carapito R, Fornecker LM, Muller L, Paul N, Tahar O, Pichot A, Tavian M, Nicolae A, Miguet L, Mauvieux L, Herbrecht R, Cianferani S, Freund JN, Carapito C, Maumy-Bertrand M, Bahram S, Bertrand F, Vallat L (2021). Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia. Leukemia 35(5):1463-1474. doi: 10.1038/s41375-021-01221-5.

Bertrand F, Aouadi I, Jung N, Carapito R, Vallat L, Bahram S, Maumy-Bertrand M (2021). selectBoost: a general algorithm to enhance the performance of variable selection methods. Bioinformatics 37:659-668. doi: 10.1093/bioinformatics/btaa855.

Minoni L, Romero-Medina MC, Venuti A, Sirand C, Robitaille A, Altamura G, Le Calvez-Kelm F, Viarisio D, Zanier K, Müller M, Accardi R, Tommasino M (2020). Transforming Properties of Beta-3 Human Papillomavirus E6 and E7 Proteins. mSphere 5:e00398-20. doi: 10.1128/mSphere.00398-20.

Schleiss C, Ilias W, Tahar O, Güler Y, Miguet L, Mayeur-Rousse C, Mauvieux L, Fornecker LM, Toussaint E, Herbrecht R, Bertrand F, Maumy-Bertrand M, Martin T, Fournel S, Georgel P, Bahram S, Vallat L (2019). BCR- associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo. Sci Rep 9(1):701. doi: 10.1038/s41598-018-36853-8.

Ainouze M, Rochefort P, Parroche P, Roblot G, Tout I, Briat F, Zannetti C, Marotel M, Goutagny N, Auron P, Traverse-Glehen A, Lunel-Potencier A, Golfier F, Masson M, Robitaille A, Tommasino M, Carreira C, Walzer T, Henry T, Zanier K, Trave G, Hasan UA (2018). Human papillomavirus type 16 antagonizes IRF6 regulation of IL-1β. PLoS Pathog 14:e1007158. doi: 10.1371/journal.ppat.1007158.

Poirson J, Biquand E, Straub ML, Cassonnet P, Nominé Y, Jones L, van der Werf S, Travé G, Zanier K, Jacob Y, Demeret C, Masson M (2017). Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin-proteasome system. FEBS J284:3171-3201. doi: 10.1111/febs.14193.

Martinez-Zapien D, Ruiz FX, Poirson J, Mitschler A, Ramirez J, Forster A, Cousido-Siah A, Masson M, Vande Pol S, Podjarny A, Travé G, Zanier K (2016). Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529:541-545. doi: 10.1038/nature16481.

Voith von Voithenberg L, Sánchez-Rico C, Kang HS, Madl T, Zanier K, Barth A, Warner LR, Sattler M, Lamb DC (2016). Recognition pf the 3’ splice site RNA by the U2AF heterodimer involves a dynamic population shift. Proc Natl Acad Sci USA 113:E7169-75.

Travé G, Zanier K (2016). HPV-mediated inactivation of tumor suppressor p53. Cell Cycle 15:2231-2.

Stutz C, Reinz E, Honegger A, Bulkescher J, Schweizer J, Zanier K, Travé G, Lohrey C, Hoppe-Seyler K, Hoppe-Seyler F (2015). Intracellular analysis of the interaction between the Human Papillomavirus type 16 E6 oncoprotein and inhibitory peptides. Plos One 10:e0132339.

Tsakogiannis D, Gortsilas P, Kyriakopoulou Z, Ruether IG, Dimitriou TG, Orfanoudakis G, Markoulatos P (2015). Site of disruption within E1 and E2 genes of HPV16 and association with cervical dysplasia. J Med Virol 87:1973-80.

Zanier K, Stutz C, Kintscher S, Reinz E, Sehr P, Bulkescher J, Hoppe-Seyler K, Travé G, Hoppe-Seyler F (2014). The E6AP Binding Pocket of the HPV16 E6 Oncoprotein Provides a Docking Site for a Small Inhibitory Peptide Unrelated to E6AP, Indicating Druggability of E6. PLoS One 9:e112514.

Tsakogiannis D, Kyriakopoulou Z, Darmis F, Ruether IGA, Dimitriou TG, Orfanoudakis G, Panotopoulou E, Markoulatos P (2014). Prevalence o HPV16 E1-1374^63nt variants in Greek women. J Med Virol 86:778-84.

Zanier K, Charbonnier S, Ould M’hamed ould Sidi A, McEwen AG, Giovanna Ferrario M, Poussin-Courmontagne P, Cura V, Brimer N, Ould Babah K, Ansari T, Muller I, Stote RH, Cavarelli J, Vande Pol S, Travé G (2013). Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins. Science 339:694-8.

Tsakogiannis D, Papadopoulou A, Kontostathi G, Ruether IGA, Kyriakopoulou Z, Dimitriou TG, Orfanoudakis G, Markoulatos P (2013). Molecular and evolutionary analysis of HPV16 E6 and E7 genes in Greek women. J Med Microbiol 62:1688-1696.

Zanier K, Ould M’hamed ould Sidi A, Boulade-Ladame C, Rybin V, Chappelle A, Atkinson A, Kieffer B, Travé G (2012). Solution structure analysis of HPV 16 E6 oncoprotein reveals a self-association mechanism required for E6-mediated degradation of p53. Structure 20:604-17.

Ould M’hamed Ould Sidi A, Ould Babah K, Brimer N, Nominé Y, Romier C, Kieffer B, Vande Pol S, Travé G, Zanier K (2011). Strategies for bacterial expression of protein-peptide complexes : Application to solubilization of papillomavirus E6. Protein Expr Purif 80:8-16.

Mackereth CD, Madl T, Bonnal S, Simon B, Zanier K, Gasch A, Rybin V, Valcarcel J, Sattler M (2011). Multi-domain conformational selection underlies pre-mRNA splicing regulation by U2AF. Nature13:408-411.

Bernard X, Robinson P, Nominé Y, Masson M, Charbonnier S, Ramirez-Ramos JR, Deryckere F, Travé G, Orfanoudakis G (2011). Proteasomal degradation of p53 by human Papillomavirus E6 oncoprotein relies on the structural integrity of p53 core domain PLoS One 6:e25981.

Fournane S, Charbonnier S, Chapelle A, Kieffer B, Orfanoudakis G, Travé G, Masson M, Nominé Y (2011). Surface plasmon resonance analysis of the binding of high-risk mucosal HPV E6 oncoproteins to the PDZ1 domain of the tight junction protein MAGI-1. J Mol Recognition 24:511-523.

Zanier K, Ruhlmann C, Melin F, Masson M, Ould M'hamed Ould Sidi A, Bernard X, Fischer B, Brino L, Ristriani T, Rybin V, Baltzinger M, Vande Pol S, Hellwig P, Schultz P, Travé G (2010). E6 proteins from diverse papillomaviruses self-associate both in vitro and in vivo. J Mol Biol 396:90-104.