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Oncogenesis and Immunotherapy

Marc Piechaczyk

Research projects

In recent years, the "Oncogenesis and Immunotherapy" team has conducted 3 projects in parallel. These aimed to better understand two severe pathologies, cancer and serious chronic viral infections, and to improve their treatments.

The Ubiquitin Family in Hematologic Malignancies

(Program directed by Guillaume Bossis)

The peptidic post-translational modifiers of the SUMO family are, like ubiquitin to which they are structurally and functionally related, reversibly conjugated to thousands of cellular proteins, the activity, function and/or fate of which they modify. In this way, SUMOylation plays a role as important as that of phosphorylation in virtually all cellular processes. In particular, it is essential for the control of gene expression and is disrupted in a variety of disease situations.

In this context, we are studying how SUMOylation, in particular through its ability to regulate gene expression programs, is involved in the response of Acute Myeloid Leukemia (AML) to therapies, as AML is a hematological malignancy with a poor prognosis whose treatment has not changed significantly in 40 years.

Figure 2 Blaste leucemique de LAM
Figure 2: Blaste leucémique de LAM

 

 

 

 

 

 

 

 

First, we showed that, in chemosensitive AML, the chemotherapeutic drugs (anthracyclines such as daunorubicin or idarubicin and nucleoside analogues such as aracytin) used in standard treatments induce rapid transcriptional reprogramming, reinforcing the pro-apoptotic effects of the DNA damages they induce. This reprogramming is preceded by a progressive and massive deSUMOylation of cellular proteins due to the ROS (Reactive Oxigen Species)- dependent inactivation of the SUMO activation enzyme E1 and -conjugation enzyme E2 (Bossis et al., 2014). This deSUMOylation is particularly rapid and important on chromatin, especially at the level of promoters and enhancers where SUMOylated proteins are highly enriched, which limits the activation of pro-proliferative and anti-apoptotic genes and facilitates cell death (Boulanger et al., in preparation). On the other hand, in chemoresistant AMLs, anthracyclines neither induce ROS production nor deSUMOylation. However, inhibition of SUMOylation by pharmacological or genetic pathways restores the ROS/SUMO axis, facilitating apoptosis of chemoresistant AMLs (Bossis et al., 2014), pointing to the possibility of a novel therapeutical approach of this deadly disease. More recently, we have shown that deregulation of SUMOylation and ubiquitylation enzyme activity is associated with AML resistance to standard chemotherapies (Gâtel et al., 2019) and might serve as a biomarker of AML response to these treatments (patent EP19305688, 2019).

We have also been interested in the role of SUMOylation in the response of AML to retinoic acid (ATRA)-based differentiation therapies. Such therapies are based on the idea that the restoration of differentiation of leukemic blasts is associated with proliferation arrest followed by cell death due to the naturally limited lifespan of differentiated myeloid cells. Differentiation therapies combining ATRA and arsenic trioxide (As2O3) are highly effective on a minor subtype of AMLs, Acute Promyelocytic Leukemia (APL; 7-10% of AMLs). However, their efficacy is very limited in the other subtypes. We have shown that inhibition of SUMOylation facilitates ATRA-induced differentiation and proliferation arrest in non-APL AMLs by activating specific genes involved in these processes (Baik et al., 2018), paving the way to another novel therapeutical approach of non-APL AMLs.

Thus, our work suggests that targeting SUMOylation might consitute a new therapeutic approach in AMsL, particularly to overcome resistance to the therapies used to treat them so far. The objectives of our current work are: (i) to better understand, at the molecular level, the role of SUMOylation in the response of AMLs to therapies (chemotherapies, differentiation therapies and epidrug-based therapies) and (ii) to validate, in preclinical models of AMLs, the efficacy of SUMOylation targeting in the treatment of AMLs, alone or in combination with existing therapies. This work is carried out in close collaboration with the Department of Clinical Hematology of the University Hospital of Montpellier.

 

Selection of publications related to this theme:

Bossis, G., Sarry, J.E., Kifagi, C., Ristic, M., Saland, E., Vergez, F., Salem, T., Boutzen, H., Baik, H., Brockly, F., Pelegrin, M., Kaoma, T., Vallar, L., Recher, C., Manenti, S., Piechaczyk, M. The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs. Cell Reports 7: 1815-1823 (2014)

 Tempé, D., Vives, E., Brockly, F., Brooks, H., de Rossi, S., Piechaczyk, M. and Bossis, G.  SUMOylation of the inducible (c-Fos:c-Jun)/AP-1 transcriptional complex occurs on target promoters to limit transcription. Oncogene doi: 10.1038/onc.2013.4 (2013)

 Baik, H., Hossein, S-M., Kowalczyk, J., Boulanger, M., Zaghdoudi, S., Salem, T., Sarry, J-E., Hicheri, Y., Cartron, G., Piechaczyk, M. and Bossis, G. Inhibition of the SUMO pathway potentiates all-trans-retinoic acid differentiation of non-promyelocytic acute myeloid leukemia. Cancer Res. doi: 10.1158/0008-5472.CAN-17-336 (2018)

Hosseini M, Rezvani HR, Aroua N, Bosc C, Farge T, Saland E, Guyonnet-Dupérat V, Zaghdoudi S, Jarrou L, Larrue C, Sabatier M, Mouchel PL, Gotanègre M, Piechaczyk M, Bossis G, Récher C, and Sarry JE. Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia. Cancer Res. 79:5191-5203. doi: 10.1158/0008-5472.CAN-19-0515 (2019)

Gatel P, Piechaczyk M, Bossis G.  Ubiquitin, SUMO and Nedd8 as therapeutic targets in cancer. Adv Exp Med Biol. 2020;1233:29-54. doi: 10.1007/978-3-030-38266-7_2. 

Gatel P, Brockly F, Reynes C, Pastore M, Hicheri Y, Cartron G, Piechaczyk M, Bossis G. Ubiquitin and SUMO as biomarkers of Acute Myeloid Leukemia response to chemotherapies. Life Science Alliance.2020. https://doi.org/10.26508/lsa.201900577

 

Transcriptional control of the aggressiveness of metastatic breast cancers

(Program directed by Isabelle Jariel-Encontre)

Transcription factors are essential molecular platforms for the integration of intra- and extracellular signals and their activity is regulated by numerous post-translational modifications. However, the molecular mechanisms by which their deregulation alters gene expression at the chromatin level to allow cancer cells to adapt to their environment and increase their aggressiveness are still poorly understood. This is particularly true for the ubiquitous AP-1 complex which is a group of dimeric transcription factors formed by members of the Fos and Jun multigenic families involved, on the one hand, in the regulation of virtually all cellular and physiological processes and, on the other hand, in the development of many pathologies.

Figure 2: Fos family protein accumulating in the nucleus (yellow) and contrasting with a protein diffusing freely between the nucleus and the cytoplasm (red)
Figure 2: Fos family protein accumulating in the nucleus (yellow) and contrasting with a protein diffusing freely between the nucleus and the cytoplasm (red)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

In this context, we are studying (i) why and how two proteins of the c-Fos proto-oncoprotein family, Fra-1 and Fra-2, contribute to the metastatic phenotype and aggressiveness of so-called triple negative breast tumors (TNBCs), where they are overexpressed and hyperphosphorylated due to perverted intracellular signaling, and (ii) to what extent this knowledge may lead to new treatments.

This question is particularly important because metastatic breast tumours are currently the leading cause of cancer death in women.

Our project is based on high-throughput transcriptomic and genomic approaches combined with the exploitation of clinical databases and functional studies of transcription and intracellular signalling. Our goals are to identify Fra-1 and Fra-2 gene targets whose protein products could constitute new pharmacological targets in the treatment of breast cancer and to elucidate the transcriptional mechanisms controlled by Fra-1 and Fra-2 proteins that could be exploited therapeutically when they are abnormally expressed.

Selection of publications related to this theme:

 Malnou CE, Brockly F, Favard C, Moquet-Torcy G, Piechaczyk M, Jariel-Encontre I. Heterodimerization with different Jun proteins controls c-Fos intranuclear dynamics and distribution. J Biol Chem. 285:6552-62. doi: 10.1074/jbc.M109.032680. (2010)

Talotta F, Mega T, Bossis G, Casalino L, Basbous J, Jariel-Encontre I, Piechaczyk M, Verde P. Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. Oncogene 29:4732-40. doi: 10.1038/onc.2010.211 (2010)

 Sayan, A.E., Stanford, R., Vick ery, R., Grigorenko, E., Diesch, J., Kulbicki, K., Edwards, R., Pal, R., Greaves, P., Jariel-Encontre, I., Piechaczyk, M., Kriajevska, M., Mellon, J.K., Dhillon, A.S., Tulchinsky, E. Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene 31: 1493-1503 (2012)

 Belguise, K., Milord, S., Galtier, F., Moquet-Torcy, G., Piechaczyk, M., Chalbos, D. The PKCtheta pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells. Oncogene 31: 4889-4897 (2012)

 Salem T, Gomard T, Court F, Moquet-Torcy G, Brockly F, Forné T, Piechaczyk M. Chromatin loop organization of the junb locus in mouse dendritic cells. Nucl. Acids Res. 41:8908-25. doi: 10.1093/nar/gkt669 (2013)

 Pérez-Benavente B, García JL, Rodríguez MS, Pineda-Lucena A, Piechaczyk M, Font de Mora J, Farràs R. (2013) GSK3-SCF(FBXW7) targets JunB for degradation in G2 to preserve chromatid cohesion before anaphase. Oncogene. 32:2189-99. doi: 10.1038/onc.2012.235 (2013)

 Moquet-Torcy G, Tolza C, Piechaczyk M, Jariel-Encontre I. Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer. Nucleic Acids Res. 42:11011-24. doi: 10.1093/nar/gku814 (2014)

 Tolza C, Bejjani F, Evanno E, Mahfoud S, Moquet-Torcy G, Gostan T, Maqbool MA, Kirsh O, Piechaczyk M, Jariel-Encontre I.  AP-1 Signaling by Fra-1 Directly Regulates HMGA1 Oncogene Transcription in Triple-Negative Breast Cancers. Mol. Cancer Res. 17:1999-2014. doi: 10.1158/1541-7786.MCR-19-0036. (2019)

Bejjani F, Evanno E, Zibara K, Piechaczyk M, Jariel-Encontre I. The AP-1 transcriptional complex: Local switch or remote command? Biochim. Biophys. Acta Rev. Cancer 1872:11-23. doi: 10.1016/j.bbcan.2019.04.003. (2019).

Vaccinal effects of passive immunotherapies based on expressed monoclonal antibodies.

(Program directed by Mireia Pelegrin)

(Also see: http://www.irmb-inserm.fr/mireia-pelegrin.html)

Monoclonal antibodies (mAbs) are the main class of biotherapeutic agents. They have applications in many diseases. However, their clinical use is far from optimal for the treatment of certain chronic diseases. In particular, and curiously, until recently, monoclonal antibodies have received very little consideration in the antiviral arsenal. Moreover, only their neutralizing capabilities have been considered despite the fact that they interact functionally with other components of the immune system. We have therefore studied whether and how mAbs are immunomodulatory agents influencing the antiviral immunity of infected hosts and, through this action, the efficacy of treatments.

Figure 3: Dendritic cells (green with blue nuclei) capturing and ingesting (red) cells infected with a retrovirus and complexed to a neutralizing monoclonal antibody recognizing the viral envelope glycoprotein expressed on the surface of these cells.
Figure 3: Dendritic cells (green with blue nuclei) capturing and ingesting (red) cells infected with a retrovirus and complexed to a neutralizing monoclonal antibody recognizing the viral envelope glycoprotein expressed on the surface of these cells.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

In vivo studies with human viruses are hardly possible due to many technical and ethical limitations. Our work is therefore conducted in a mouse model of acute myeloid leukemia based on the infection of immunocompetent mice with a lethal retrovirus (FrCasE) followed by their treatment with neutralizing antiviral mAbs. We have thus discovered that short courses of treatment with mAbs can induce a lifelong antiviral immune protection ("vaccine-like" effect) by enhancing humoral and cytotoxic T (CTL) immune responses under appropriate immunotherapy conditions. The therapeutic consequences of this observation are potentially high and should be considered for future passive immunotherapies of life-threatening chronic infections such as HIV or HCV.

The main questions we have recently addressed concerned the cellular and molecular mechanisms responsible for the induction of such a protective antiviral vaccine effect, with a particular focus on the interactions between immune complexes formed during immunotherapy and the different cell types of the immune system.

For this purpose, vaccination experiments were conducted in genetically modified mice, as well as in ex vivo tests involving various immune cells. We also extend our observations to the treatment of HIV infections.

Since 2019, this project is continued at the Institute of Regenerative Medicine in Montpellier (IRMB; U INSERM 1183) where its leader, Mireia Pelegrin, has initiated a new research group. Her web page can be consulted at: http://www.irmb-inserm.fr/mireia-pelegrin.html

Selection of publications related to this theme:

Michaud, H.A., Gomard, T., Gros, L., Thiolon, K., Nasser, R., Jacquet, C., Hernandez, J., Piechaczyk, M., Pelegrin, M. A. Crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy. PLoS Pathog 6: e1000948 (2010)

 Nasser R, Pelegrin M, Michaud HA, Plays M, Piechaczyk M, Gros L. Long-lasting protective antiviral immunity induced by passive immunotherapies requires both neutralizing and effector functions of the administered monoclonal antibody. J Virol. 2010 Oct;84(19):10169-81. doi: 10.1128/JVI.00568-10.

 Nasser, R., Pelegrin, M., Plays, M., Gros, L., Piechaczyk, M. Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies. Blood 121: 1102-1111 (2013)

 Pelegrin M, Gros L, Piechaczyk M. Vaccine-like effects of antiviral monoclonal antibodies: a novel therapeutic perspective? Med Sci 29:457-60. doi: 10.1051/medsci/2013295005. (2013)

 Pelegrin, M., Naranjo-Gomez, M. and Piechaczyk, M. Antiviral monoclonal antibodies: are they just neutralizing agents? Trends Microbiol. 23:653-65. doi: 10.1016 (2015)

 Lambour J, Naranjo-Gomez M, Piechaczyk M, Pelegrin M. Converting monoclonal antibody-based immunotherapies from passive to active: bringing immune complexes into play. Emerg Microbes Infect. 5:e92. doi: 10.1038/emi.2016.97 (2016)

 Naranjo-Gomez M, Lambour J, Piechaczyk M, Pelegrin M. Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies. J. Clin. Invest. Insight. 3: pii: 97339. doi: 10.1172/jci.insight.97339 (2018)

 

Members

Team leader

Marc PIECHACZYK

Chercheur DR1

(+33) 04 34 35 96 68

216 - 201

Dana AKL

Stagiaire

+33 (0)4 34 35 96 71

Guillaume BOSSIS

Chercheur

(+33) 04 34 35 96 70

216

Frederique BROCKLY

IE-Recherche

(+33) 04 34 35 96 70

M214

MEHULI CHAKRABORTY

Doctorant

+33 (0)4 34 35 96 46

201

Marion DETOLEDO

Chercheur

(+33) 04 34 35 96 71

RDC04

Ludovic GABELLIER

Doctorant

+33 (0)4 34 35 96 71

201

Isabelle JARIEL

CRHC

(+33) 04 34 35 96 68

216

Francesco LEONETTI

Stagiaire

+33 (0)4 34 35 96 68

216

Clara RECASENS-ZORZO

Post-Doc

+33 (0)4 34 35 96 49

214

Denis TEMPé

Chercheur

+33 (0)4 34 35 96 68

216

Selected Publications

More information

Funding

Our team benefits, or has benefited, from funding from :: EC FP7, INCa, l'ANR, Fondation ARC, GEFLUC-LR, Cancéropôle GSO, Région Languedoc-Roussillon, Fédération Leucémie Espoir, Association Laurette Fugain, I-Site Montpellierain MUSE, etc.. It is endorsed by the Ligue Nationale contre le Cancer.

 

Interactions

NETWORKS AND COLLABORATIONS

Our projects are, or have always been, conducted in collaboration with local, national and/or foreign teams. In particular, we can mention the European COST Network "Proteostasis", the "UPSsream" ITN from the Marie Curie-Sklodowska Program, the "EpiGenMed" Labex, the "MAbImprove" Labex, the "Montpellier Cancer" SIRIC and the "EvoCan" FHU.

 

 

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Team Overview
Model organism studied
Man and mice. Primary tumors.
Biological process
Carcinogenesis, leukemogenesis, oncogenesis, transcription, post-translational modifications by ubiquitin-likes, monoclonal antibody immunotherapies, viral pathologies.
Biological techniques
Cell and molecular biology, immunology, high through-put genomics and proteomics, bioinformatics