Mercredi 16 janvier 2019, 11h00 : Séminaire MAbImprove

Nicolas Boissel 


Departement d'Hématologie, Hopital Saint-Louis et Université Paris Diderot, Paris, France


“Development of immunotherapy for the treatment of acute myeloid leukaemia”


Contact: watier@med.univ-tours.fr


Jeudi 17 Janvier 2019, 14h

Cyril Esnault

IGMM, CNRS Montpellier


"How do environmental cues control cell behaviour or fate decision programs? Learning from Rho and Ras transcriptional effectors."


contact: claude.sardet@inserm.fr


Short presentation


Environmental cues such as growth factor, hormone, nutrient and cytokine concentrations are essential in regulating cell behaviour and differentiation processes. Cells integrate these external stimuli through signalling pathways to mediate their response. Aberrant signalling processes are a common feature of diseases such as cancer, so understanding them is critical for the development of therapeutic interventions. In our previous work, we have focussed on the Ras and Rho pathways, whose activity is disrupted in a large proportion of human cancers. The Ras pathway is instrumental in control of cancer cell proliferation, while the Rho pathway is a critical player in metastasis. The model we have used is the fibroblast serum response, a classical model for cell cycle re-entry and wound healing. The transcriptional response to serum is in its large part controlled by the Serum Response Factor (SRF). SRF functions in partnership with members of two families of signal-regulated cofactors: the MRTFs (myocardin-related transcription factors; MRTF-A, MRTF-B, and myocardin itself) and the TCF (ternary complex factor) family of Ets domain proteins (SAP-1, Elk-1, and Net). The MRTFs, which bind G-actin, respond to fluctuations in G-actin concentration induced by Rho GTPase, while TCF activity is controlled by Ras–ERK signaling. Investigating at the genomic scale the serum response, we have described how transcription and epigenetic rearrangement are regulated. We have defined the regulatory elements and genes that are regulated by Rho and Ras signalling pathways and explored how SRF and its coactivators modulate the circadian rhythm, the response to mechanical signals and control the balance between cell proliferation and invasion. In addition to soluble biochemical messengers, cells also need to respond to physical constraints i.e. external forces or mechanical cues such as stretch, compression and changes in the stiffness of the extracellular matrix (ECM). Although they are of critical patho-physiological importance, the molecular events elicited in response to mechanical cues have remained elusive. Indeed, during oncogenesis progression, the extracellular matrix (ECM) surrounding the tumour is stiffening due to matrix remodelling. It can arise from fibrosis or in response to tumour compression and cytoskeletal tension. Mechanosensation and tumour progression are paired: ECM stiffening supports the metastatic program and promotes cytoskeletal rearrangements required during cell invasion. Moreover, normal cellular differentiation has also been shown to be critically dependent on integration of mechanical cues. Mesenchymal Stem Cells (MSCs) are multipotent cells, which are able to differentiate into a variety of connective tissues. In this process, mechanical cues are determinant drivers of the lineage choice: the bone marrow is composed of discrete regions of variable matrix compositional properties, exposing MSCs to low tension conditions favour adipogenesis, while higher tensions favour myogenesis and the highest tensions drive differentiation to osteogenesis. Similarly, physical cues from the microenvironment regulate epidermal stem cell fate decisions. In that case, actin cytoskeleton rearrangement induces keratinocyte differentiation. However, while Rho and Ras signalling pathways have been identified in the response to matrix stiffness, how mechanosensation signals are transduced, integrated by the cell, how they impact on the transcriptional or epigenetic programs, what are the transcription factor networks involved apart from SRF/MRTF and YAP/TAZ and how such cues regulate cell behaviour are still open questions that I further aim to address.



Mercredi 6 février 2019, 10h00. Séminaire MabImprove

Mary Poupot 


Centre de Recherche en Cancérologie de Toulouse, Toulouse


"Development of an anti-tumor associated macrophage antibody for cancer immunotherapies”


Contact: valerie.gouilleux@univ-tours.fr


In short:

Among cellular components of the Tumor microenvironment (TEM), tumor associated macrophages (TAM) are modified macrophages educated by the tumor to favor its development. Being able to eliminate or deactivate these cells is a challenge today in anticancer therapies. We recently produced a new antibody specifically directed against human TAM. We chose the chronic lymphoblastic leukaemia (CLL) as model which is a malignant hemopathy with only 50% of complete remission and a deleterious effect of the treatment on the immune system of the patients. The resistance of the residual disease is due to the intrinsic properties of cancer cells but also to their close contact in lymph nodes with nurse like cells (NLC). We defined these cells as CLL’s TAM, infiltrating the lymph nodes and associated with the aggressiveness of the disease in a contact dependant manner. Target these cells would be a new therapeutic insight in cancer. NLC are easily produced in vitro by the culture of PBMC from CLL patients by the differentiation of monocytes in contact with CLL cells. After a mouse immunization with these NLC, we selected one antibody specifically targeting NLC (patent Inserm). This antibody called 6-25 does not bind to leukemic cells or healthy B and T lymphocytes and monocytes. Moreover, immunohistochemistry and immunofluorescence analyses of different human tumors proved that our antibody can target different TAM. In parallel, we found that the target of the 6-25 mAb is the sideroflexin 3 (patent Inserm). The advantage of our anti-SFXN3 antibody is the specificity of TAM targeting with a promising future in anticancer therapies.

Mercredi 13 Février 2019, 14h; SIRIC Cancer Highlight Seminar

Sophie Lelièvre


Purdue University Center for Cancer Research, West Lafayette, In. USA


“Cancer-on-a-chip to study progression mechanisms and anticancer drug sensitivity”


Contact: charles.theillet@inserm.fr


The design of tissue-chips is gaining momentum because these engineered cell culture platforms provide highly controlled microenvironments for the study of normal and diseased tissues. I will discuss how tissue-chips can be used to recreate the organ geometry necessary for the full recapitulation of cell behavior, using the example of carcinomas that develop within ducts. Indeed, the curved environment of hemichannels confers mechanical constraints that influence drug sensitivity. So far, this system is surpassing other cell culture models for the assessment of drug efficacy at the cancer cell level, as shown with the example of triple negative breast cancer. Another use of tissue-chips is to create gradients of molecules in the microenvironment that are conducive to tissue heterogeneity responsible for cancer progression and drug resistance. We have designed a gradient-on-a-chip with which we demonstrated that increased matrix stiffness associated with breast cancer progression lowers the concentration at which progression promoting oxidizing molecules worsen cancer phenotypes. Throughout the seminar basic principles of tissue-chip design will be presented and the applications of cancers-on-a-chip for precision medicine will be highlighted.

Vendredi 15 février, 14h

Eva Gonzalez Suarez


IDIBELL Bellvitge Biomedical Research Institute, Barcelone


"Novel therapeutic opportunities for breast cancer treatment"


contact: charles.theillet@inserm.fr

Vendredi 22 février 2019, 14h

Valerio Iebba


INSERM U1015 Gustave Roussy, Villejuif/Université de Rome La Sapienza, Rome


"Intestinal microbiota and Escherichia coli involvement in inflammation and cancer"

Contact: claude.sardet@inserm.fr

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