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CANTHER (UMR-9020/1277)

Our research team, entitled « Factors of persistence of leukemic cells », is devoted to the discovery of factors that contribute to long-term persistence of leukemia cells, such as tumor dormancy, and to the characterization of predictive genomic markers of hematological malignancies evolution. 

The team is located at the Lille Institute for Cancer Research (IRCL) for our cell biology research, as well as in the Hematology and High Throughput Technologies Department of Lille University Hospital for the access to its patient tumor cell bank and for our translational molecular biology activities.  

The team has historic ties with the Clinical Hematology Department, the Hematology Laboratory and the Cytogenetics Department of the hospital. Several members of our team are affiliated to the University Hospital and several research projects directly stem from this high degree of integration.

Salomon Manier
Prof. Salomon Manier

Head of Entity

Nicolas Duployez
Dr. Nicolas Duployez
Claude Preudhomme
Prof. Claude Preudhomme
Jerome Kluza
Dr. Jerome Kluza

Contact

Email : SALOMON.MANIER@chu-lille.fr

Laboratoire Canther
UMR9020 CNRS – UMR1277 Inserm Université de Lille – CHU Lille
1, place de Verdun
59045 LILLE Cedex - France

Website

  • MDS/MPN syndromes
  • Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions
  • Acute undifferentiated leukemia or Mixed Phenotype Acute Leukemia (MPAL)
  • Waldenström Macroglobulinemia (WM)
  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndromes (MDS)
  • Myeloid sarcoma
  • Leukemia predisposition syndromes

Eradication of the last tumor cell has been the holy grail of cancer research for decades. The idea was that if only a few persistent cancer cells remained in the body, relapse would inevitably occur. Thus, understanding the mechanisms that allow for the long-term persistence of these cells would help to avoid relapses. To address the question of persistence in human leukemia, we have built our research team around three strategic scientific axes. 

Tumour dormancy and long-term persistence factors in leukemia

The first one was aimed at discovering, using experimental models and patient cohorts, factors that govern tumor dormancy and long term persistence of minimal residual disease (MRD) in leukemia. 

Results have specifically pinpointed the role of immunoescape, stemness and tumor metabolism, and their modifications in response to treatments including chemotherapy and targeted therapies such as tyrosine kinase inhibitors.

 

Genomic markers of hematological malignancies

The second axis was dedicated to the systematic evaluation of new genomic markers of prognosis in hematological malignancies, notably AML, MDS, and Waldenstrom’s disease. Researchers target the characterization of predictive markers of treatment failure and relapse in hematological malignancies that can be easily translated into the daily routine. Biobanking of numerous national prospective clinical trials is performed by our team at the tumor cell bank. This axis has recently evolved toward a functional characterization of leukemia cells, such as drug resistance and leukemia stemness, which are currently investigated in prospective patient cohorts from national study groups such as ALFA, GFM and CONECT-AML. 

New therapeutic strategies

The third axis investigates new therapeutic strategies to target MRD. We develop new drugs that target transcription factor/DNA interaction in collaboration with chemists to target protein/protein interactions in dormant tumor cells as well as synthetic immunotherapies.

 

  • Targeted therapy
  • Immunotherapy
  • CAR-T cells

Scientific

  • Definition of genomic prognostic markers for AML and MDS
  • Contribution to the validation of the LCS17 stemness score in acute myeloblastic Leukemias in children and adults
  • Identification of germline genetic lesions predisposing to the development of AML and MDS
  • Involvement of mitochondrial metabolism in the therapeutic effect of tyrosine kinase inhibitors
  • Identification of the mechanism by which CDK8 controls STAT3
  • Identification of compounds that block PD-L1/PD-1 interaction (see patent)
  • Identification of small molecules targeting HOXA9 in AML
  • Development of experimental models of tumour dormancy

Medical

  • Identification of new genetic abnormalities defining AML 
  • Definition of genomic prognostic markers for AML for treatment stratification
  • Validation of markers of residual disease in AML to guide therapy and haematopoietic stem cell transplantation

 

  • Vasseur L, Fenwarth L, Lambert J, de Botton S, Figeac M, Villenet C, Heiblig M, Dumas PY, Récher C, Berthon C, Lemasle E, Lebon D, Lambert J, Terré C, Celli-Lebras K, Dombret H, Preudhomme C, Cheok M, Itzykson R, Duployez N. LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study. Blood Adv. 2023;7(15):4024-4034. doi:10.1182/bloodadvances.2023010155
  • Duployez N, Vasseur L, Kim R, Largeaud L, Passet M, L’Haridon A, Lemaire P, Fenwarth L, Geffroy S, Helevaut N, Celli-Lebras K, Adès L, Lebon D, Berthon C, Marceau-Renaut A, Cheok M, Lambert J, Récher C, Raffoux E, Micol JB, Pigneux A, Gardin C, Delabesse E, Soulier J, Hunault M, Dombret H, Itzykson R, Clappier E, Preudhomme C. UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia. Leukemia. 2023;37(6):1245-1253. doi:10.1038/s41375-023-01906-z
  • Leleu-Chavain N, Regnault R, Ahouari H, Le Biannic R, Kouach M, Klupsch F, Magnez R, Vezin H, Thuru X, Bailly C, Goossens JF, Millet R. Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents. Molecules. 2022 May 21;27(10):3316. doi: 10.3390/molecules27103316. PMID: 35630791; PMCID: PMC9143004.
  • Le Biannic R, Magnez R, Klupsch F, Leleu-Chavain N, Thiroux B, Tardy M, El Bouazzati H, Dezitter X, Renault N, Vergoten G, Bailly C, Quesnel B, Thuru X, Millet R. Pyrazolones as inhibitors of immune checkpoint blocking the PD-1/PD-L1 interaction. Eur J Med Chem. 2022 Jun 5;236:114343. doi: 10.1016/j.ejmech.2022.114343. Epub 2022 Apr 4. PMID: 35429911.
  • Shaik FA, Lewuillon C, Guillemette A, Ahmadian B, Brinster C, Quesnel B, Collard D, Touil Y, Lemonnier L, Tarhan MC. Pairing cells of different sizes in a microfluidic device for immunological synapse monitoring. Lab Chip. 2022 Mar 1;22(5):908-920. doi: 10.1039/d1lc01156a. PMID: 35098952.
  • Farfariello V, Gordienko DV, Mesilmany L, Touil Y, Germain E, Fliniaux I, Desruelles E, Gkika D, Roudbaraki M, Shapovalov G, Noyer L, Lebas M, Allart L, Zienthal-Gelus N, Iamshanova O, Bonardi F, Figeac M, Laine W, Kluza J, Marchetti P, Quesnel B, Metzger D, Bernard D, Parys JB, Lemonnier L, Prevarskaya N. TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence. Nat Commun. 2022 Feb 17;13(1):956. doi: 10.1038/s41467-022-28597-x. PMID: 35177596; PMCID: PMC8854551.
  • Kluza J, Peugnet V, Daunou B, Laine W, Kervoaze G, Rémy G, Loyens A, Maboudou P, Fovez Q, Grangette C, Wolowczuk I, Gosset P, Garçon G, Marchetti P, Pinet F, Pichavant M, Dubois-Deruy E. A New Strategy to Preserve and Assess Oxygen Consumption in Murine Tissues. International Journal of Molecular Sciences. 2022;23(1):109. doi:10.3390/ijms23010109
  • Duployez N, Largeaud L, Duchmann M, Kim R, Rieunier J, Lambert J, Bidet A, Larcher L, Lemoine J, Delhommeau F, Hirsch P, Fenwarth L, Kosmider O, Decroocq J, Bouvier A, Le Bris Y, Ochmann M, Santagostino A, Adès L, Fenaux P, Thomas X, Micol JB, Gardin C, Itzykson R, Soulier J, Clappier E, Recher C, Preudhomme C, Pigneux A, Dombret H, Delabesse E, Sébert M. Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood. 2022;140(7):756-768. doi:10.1182/blood.2021015328
  • Fenwarth L, Thomas X, de Botton S, Duployez N, Bourhis JH, Lesieur A, Fortin G, Meslin PA, Yakoub-Agha I, Sujobert P, Dumas PY, Récher C, Lebon D, Berthon C, Michallet M, Pigneux A, Nguyen S, Chantepie S, Vey N, Raffoux E, Celli-Lebras K, Gardin C, Lambert J, Malfuson JV, Caillot D, Maury S, Ducourneau B, Turlure P, Lemasle E, Pautas C, Chevret S, Terré C, Boissel N, Socié G, Dombret H, Preudhomme C, Itzykson R. A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia. Blood. 2021;137(4):524-532. doi:10.1182/blood.2020005524
  • Touil Y, Latreche-Carton C, Bouazzati HE, Nugues AL, Jouy N, Thuru X, Laine W, Lepretre F, Figeac M, Tardivel M, Kluza J, Idziorek T, Quesnel B. p65/RelA NF-κB fragments generated by RIPK3 activity regulate tumorigenicity, cell metabolism, and stemness characteristics. J Cell Biochem. 2022;123(3):543-556. doi:10.1002/jcb.30198

Research infrastructures

Differential Scanning

Fluorimetry NanoDSF

Integrative Chemistry-Biology Platform (ICBP)

Scientific Director : Xavier Thuru (xavier.thuru@univ-lille.fr). Technical Manager  Romain Magnez (romain.magnez@inserm.fr).

NanoDSF s the method of choice for a quick and precise measure of protein stability. It detects changes in fluorescence of tryptophan, a hydrophobic amino acid found in proteins. Such fluorescence is strongly dependent on the close environment of the amino acid. In a protein with a correct conformation, it is located in the hydrophobic heart of the protein and is protected from the aqueous environment of the solvant. During unfolding, tryptophan becomes exposed, something that alters fluorescence. Protein unfolding can thus be recorded through an approach without any pre-labelling.

Tycho NT.6 from NanoTemper Technologies GmbH (Munich, Germany) is a unique automated tool for the measurement of relative quality, thermal stability, similarity and functionality of native protein samples in solution. In 3 minutes, it provides detailed information about presence, quality and functionality of proteins.

This equipment is optimal for protein preservation methods development and for the degradation control and it allows a fast screening of interactions.

 

Molecular interaction

 

Integrative Chemistry-Biology Platform (ICBP)

Scientific Director : Xavier Thuru (xavier.thuru@univ-lille.fr). Technical Manager  Romain Magnez (romain.magnez@inserm.fr).

Based on the principles of thermophoresis, MicroScaleThermophoresis permits the detection of molecular interactions between biomolecules of different physicochemical nature, purified or not.

The equipment we have acquired (Monotih NT.115) allows the detection of variations in the motility of a fluorescent molecule (naturally or through fluorescent labeling) submitted to a temperature micro-gradient created in a capillary, in the presence of growing concentrations of a specific interactant. The exploitation of a compound’s thermophoretic properties for molecular interaction studies is innovative.

 

FRET / TR-FRET 

 

Interaction analysis platform (FRET and TR-FRET)

Scientific Director : Xavier Thuru (xavier.thuru@univ-lille.fr). Technical Manager Romain Magnez (romain.magnez@inserm.fr).

The network of protein interactions is of major importance in higher organisms. The sequencing of the genome has revealed a relatively small number of genes, leading to the suggestion that biological complexity is not reflected in the number of genes, but in the number of physiologically relevant protein-protein interactions. Several techniques are capable of detecting protein-protein interactions in a dynamic manner. Amongst these, FRET (Fret) based techniques.

The platform thus offers a set of tools, technologies and associated skills for the quantitative and qualitative analysis of protein/protein interactions. The platform is complementary to the structural biology platforms and the physicochemical interaction analysis platforms.

We have our own plasmids allowing the grafting of fluorophores (CFP and YFP) to the Cter or Nter of your protein of interest for classical FRET and the possibility of carrying out TR-FRET with tagged proteins (his, biotinylated, etc.).

Genomics

 

Genomic analysis platform for myeloid malignancies

Contacts : Claude Preudhomme (claude.preudhomme@chu-lille.fr) & Dr. Nicolas Duployez (nicolas.duployez@chu-lille.fr).

The platform has expertise in the genetic annotation of large retrospective or prospective cohorts of patients with myeloid malignancies and the detection of clonal hematopoiesis. It is involved in genomic analyses for cooperating groups (ALFA, GFM) of adult and pediatric (CONECT-AML) patients. Analyses include diagnostic annotations as well as residual disease monitoring.
Biological samples  

Essai clinique

LAM

Biological Resources from ALFA trials (ALFA property).

 

Registry/observatory

LAM

Hauts de France AML Observatory (Prof. Claude Preudhomme).

 

Registry/observatory

Clinical data

Hauts de France LAM Observatory (Prof. Claude Preudhomme).

 

Partnership research offers

COHORT GENOMIC ANNOTATION PLATFORM FOR PHASE I TO III CLINICAL TRIALS (AML/MDS/LEUKEMIA PREDISPOSITION SYNDROMES)

PLATFORM FOR GENOMIC ANNOTATION AND RETROSPECTIVE ANALYSIS OF AML COHORTS

Partners

Academics

Affiliation

CHU de Lille CNRS Inserm Université de Lille