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Oncogenesis and Immunotherapy

Marc Piechaczyk

Research projects

We are conducting three parallel projects aiming at better understanding two life-threatening diseases, cancer and severe chronic viral infections, as well as improving their treatments.

1.Transcriptional control of metastatic breast cancer aggressiveness

(Co-led by Isabelle Jariel-Encontre and Marc Piechaczyk)

Transcription factors constitute essential molecular platforms for the integration of intra- and extracellular signals and their activity is regulated by numerous of post-translational modifications. Yet, the molecular mechanisms whereby their deregulation alters gene expression at the chromatin level to permit adaptation of cancer cells to their environment and to strengthen their agressiveness are still ill-defined. This is particularly true for the ubiquitous AP-1 complex, which is a group of dimeric transcription factors made up of the members of the Jun and Fos multigene families implicated, on the one hand, in the regulation of virtually all cell and physiological processes and, on the other, in the development of various pathologies.

Figure 1: Protein of the Fos family accumulating in the nucleus (yellow), contrasting with a protein freely diffusing between the nucleus and the cytoplasm (red)

In this context, we are addressing why and how two proteins related to the c-Fos proto-oncoprotein, Fra-1 and Fra-2, contribute to the metastatic phenotype and agressiveness of the so-called triple negative breast tumors where they are overexpressed and hyperphosphorylated due to perverted cell signaling and to which extend this knowledge can be used to improve treatments.

This question is particularly important, as metastatic breast cancer is currently the main cause of death by cancer amongst women.

Our project relies on high throughput transcriptomic and genomic approaches that are combined with both the exploitation of cancer databases and studies of transcription and signaling. Our aims are to identify Fra-1- and Fra-2 target genes whose protein products may constitute novel pharmacological targets in breast cancer treatment and to elucidate the transcriptional mechanisms controlled by abnormally expressed Fra-1 and -2 that may be exploited therapeutically.

Publications related to this theme

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)

Tempé, D., Vives, E., Brockly, F., Brooks, H., de Rossi, S., Piechaczyk, M. (*) and Bossis, G(*). (2013) 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 (*) co-senior authors

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 Rep 7: 1815-1823 (2014) (* co-senior authors)

2.Role of SUMO in myeloid differentiation and chemosensitivity versus chemoresistance of Acute Myeloid leukemia

(Co-led by Guillaume Bossis and Marc Piechaczyk)

The peptidic post-translational modifiers of the SUMO family are, like ubiquitin to which they are structurally and functionally related, conjugated reversibly to thousands of cell protein substrates, of which they modify the activity, function and/or fate. In this way, SUMOylation plays a role as important as phosphorylation in virtually all cellular processes.

In particular, it has a paramount role in the control of gene expression and is deregulated in numerous pathologies

Figure 2: Leukemic AML blast

In this context, we are addressing how SUMOylation, in particular through its ability to regulate gene expression programs, is involved in myeloid differentiation and contributes to chemosensitivity/chemoresistance of Acute Myeloid Leukemia (AML), AMLs being hematomalignancies with dismal outcome and whose treatment has not significantly changed for the past 40 years. We have recently shown that the chemotherapeutics used in the clinic induce a fast and massive deSUMOylation of cellular proteins in chemosensitive AML cells, which contributes to the induction of apoptosis. This occurs via activation of the so-called ROS-SUMO axis discovered by one of us (Bossis and Melchior. Mol. Cell 21:349-57 2006) whereby the reactive oxygen species (ROS) produced by drug-activated NADPH oxidase inactivate the first two enzymes of the SUMOylation cycle by promoting the formation of a disulphide bond between their catalytic cysteines. In contrast, the ROS-SUMO axis is anergized in chemoresistant AML cells but its reactivation by pharmacological or genetic means restore cell death, opening novel therapeutical possibilities.

By combining large-scale proteomic, genomic and transcriptomic approaches to functional studies in in vitro and in vivo in mouse pre-clinical models, as well as using patient samples and exploiting cancer databases, we are aiming at elucidating how the ROS-SUMO axis impact myeloid differentiation and contribute to chemosensitive AML cell death. This knowledge will be essential to initiate long-awaited novel therapeutical strategies of chemoresistant AMLs and to develop prognosis assays helping clinical decisions.

Publications related to this theme

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)

Tempé, D., Vives, E., Brockly, F., Brooks, H., de Rossi, S., Piechaczyk, M. (*) and Bossis, G(*). (2013) 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 (*) co-senior authors

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 Rep 7: 1815-1823 (2014) (* co-senior authors)

 

3.Vaccine-like effects of passive monoclonal antibody-based immunotherapies

(Co-led by Mireia Pelegrin and Marc Piechaczyk)

Monoclonal antibodies are the main class of biotherapeutics with applications in many diseases. Yet, their use in the clinic is currently far from optimal for long-term treatment of certain chronic diseases. In particular and curiously, mAbs have little been considered in the antiviral arsenal till recently and only their neutralizing activity has been considered despite the fact that they interact functionally with other components of the immune system. We are therefore addressing whether and how antiviral mAbs constitute immunomodulatory agents influencing the endogenous antiviral immunity of infected hosts and, thereby, the long-term efficacy of treatments.

Figure 3: Dendritic cells (green with blue .nuclei) capturing and ingesting cells (red) infected with a retrovirus and complexed by a neutralizing monoclonal antibody directed to the viral glycoprotein expessed at the surface of these cells

In vivo studies with human viruses being difficultly possible due to many technical and ethical limitations, this work is conducted in an acute myeloid leukemia mouse model based on infection of immunocompetent mice by a the lethal retrovirus (FrCasE) followed by treatment with neutralizing antiviral mouse mAbs.

Using it, we have recently discovered that short mAb treatments can induce life-long protective immunity ("vaccine-like effects") by enhancing the host humoral and cytotoxic T lymphocyte (CTL) responses under appropriate conditions of immunotherapy. The therapeutical consequence of this observation is potentially high and will have to be considered for future passive immunotherapies of life-threatening infections by persistent viruses such as HIV or HCV.

The paramount questions we are now facing are the cellular and molecular mechanisms responsible for the induction of such a protective antiviral immunity, with a particular emphasis on the interactions between immune complexes formed during the immunotherapy and the various immune cell types. This is addressed in vaccination experiments conducted in different genetically engineered mice lines, as well as in various ex vivo assays involving immune cells of various types. We are also currently extending our observations to the treatment of HIV infections.

Publications related to this theme

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)

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

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)

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) (* co-senior authors)

Members

Team leader

Marc PIECHACZYK

Chercheur DR1

(+33) 04 34 35 96 68

216 - 201

Fabienne BEJJANI

Post-Doc

+33 (0)4 34 35 96 68

216

Guillaume BOSSIS

DR2

(+33) 04 34 35 96 70

216

Mathias BOULANGER

Doctorant

+33 (0)4 34 35 96 70/71

216

Frederique BROCKLY

IE-Recherche

(+33) 04 34 35 96 70

M214

MEHULI CHAKRABORTY

Doctorant

+33 (0)4 34 35 96 46

201

Emilie EVANNO

Post-Doc

+33 (0)4 34 35 96 68

Ludovic GABELLIER

Doctorant

+33 (0)4 34 35 96 71

201

Isabelle JARIEL

CRHC

(+33) 04 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 receives, or has received, funds from the EC FP7, the INCa, the ANR, the Fondation ARC, the GEFLUC-LR, the GSO Cancrropole, the Région Languedoc-Roussillon, etc. It also has been endorsed by the National League against Cancer

 

Interactions

Our projects are conducted, and have always been conducted, in collaboration with other French and/or foreign teams. We are part of the European COST network "Proteostasis", the "UPSstream" 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