DEPARTMENTS AND TEAMS / Signaling of tumoral escape / 
BMP, tumoral niche & resistance

CONTACT

Véronique Maguer-Satta, PhD
Team leader
veronique.maguer-satta@lyon.unicancer.fr
+33 478 78 29 07

Cheney D, 4th floor
Centre Léon Bérard
28 rue Laennec
69373 Lyon Cedex 08
France

GUYOT Boris

Researcher, CR1 CNRS
boris.guyot@lyon.unicancer.fr

DELAY Emmanuel

Surgeon, PH Centre Léon Bérard (CLB)
emmanuel.delay@lyon.unicancer.fr.fr

NICOLINI Franck Emmanuel

Hematologist, PH Centre Léon Bérard
franck-emmanuel.nicolini@lyon.unicancer.fr

BELHABRI Amine

Hematologist, PH Centre Léon Bérard
amine.belhabri@lyon.unicancer.fr

VOELTZEL Thibault

Researcher, IR1, INSERM
thibault.voeltzel@lyon.unicancer.fr

LEFORT Sylvain

Researcher, PostDoc, INSERM
sylvain.lefort@lyon.unicancer.fr

JEANPIERRE Sandrine

Research Assistant, Technicienne Centre Léon Bérard
sandrine.jeanpierre@lyon.unicancer.fr

GEISTLICH Kevin

Research assistant, IE, INSERM
kevin.geistlich@lyon.unicancer.fr

FLORES-VIOLANTE Mario

PhD Student
qfbmarioflores@hotmail.com

JUNG Nora

PhD Student
jung_nora@yahoo.fr

ARIZKANE Kawtar

PhD student
kawtar.arizkane@gmail.com

Voir les objectifs et projets Voir les publications

Main International Collaborations:

Pr Gao Wei-Qiang, Renji Hospital Stem cell research center, Shanghai, China

Dr Zhu Helen He, Shanghai Jiao Tong University, Shanghai, China

Dr Adam Mead, University of Oxford, UK

Dr Vignir Helgason, University of Glasgow, UK

Pr Alba Hernandez, Universitat Autonoma de Barcelona, Espana

 

Main National Collaborations :

Pr Olivier Herault, Université de Tours

Dr Olivier Hyrien Institut Curie, Orsay

Dr Philippe Juin, Université de Nantes

Dr Nathalie Mazure, Université de Nice

Pr Catherine Picart, Université de Grenoble

Dr Olivier Gandrillon Université de Lyon

Dr Jean-Paul Rieu, Université de Lyon

Dr Charlotte Rivière, Université de Lyon

Dr Christophe Caux, CRCL

Dr Muriel Le Romancer, CRCL

Dr Patrick Mehlen, CRCL

Dr Pierre Saintigny, CTCL

 

National and International Network :

GDR ”Micronit”

FI-LMC

BIOSYL

Halifax Project

 

OBJECTIVES

The projects of our lab focus on Bone Morphogenetic Protein (BMP) family members, stem cells, and the tumor niche. We study the effect of the tumor environment on Cancer Stem Cells (CSCs) and their resistance to treatment, using epithelial tumour models and haematopoietic models. Our approach relies on analyzing and modulating the expression of these BMP family members and characterizing their functions. We are developing projects subjecting cancer stem cells to different conditions, which will allow us to evaluate the impact of their interactions with the microenvironment on their ability to resist treatment. We are also studying the functional consequences, in terms of drug response, of interactions between CSCs and cellular or structural components of the tumor niche, by integrating the physical and environmental parameters with, for example, the mechanical constraints.

PROJECT

Previous work

Our work has led to a number of advances in the field of Bone Morphogenic Proteins (BMPs) and stem cells (SCs).  Our work focuses on the hematopoietic system and the mammary gland. We have shown that FLRG regulates hematopoietic stem cells (HSC) by blocking members of the TGFβ family (Activin and certain BMPs), or directly by promoting the regulation of HSCs through adhesion to fibronectin. BMP4 alone regulates the entire megakaryopoiesis, for example mediated by Thrombopoietin (TPO), the effects of which are largely mediated by the autocrine BMP loop. We were further able to demonstrate that chemotherapies alter the relationship between the SC and its microenvironment, the so-called niche. We have shown that in chronic myeloid leukemia (CML), Twist1 is a predictive marker and plays a role in drug resistance. To analyze the epithelial system of the breast, we have developed a simple strategy to isolate human mammary SCs and identified a key role for the enzyme CD10 and β1 integrins in their regulation by their niche, further showing that CD10 is a marker for stem and early progenitor cells that form spheres.

 

Figure Legend.
(A) Mammopshere obtained from primary human mammary epithelial cells isolated from reduction mammoplasty.

(B) Immunofluorescent staining of keratin 14 of a mammosphere.
(C) Hematopoietic stem cell in its niche. (source: Internet Google Image) 
(D) Terminal ductal lobular unit assay. Phase contrast image of 3D structures obtained from mammary stem and progenitor cells grown in matrigel (left) and H&E staining of a cross section of a lobular unit (right).
(E) Erythroid (top) and megakaryocyte (bottom) colonies derived from human hematopoietic stem cells.

 

 

Overview of projects

From a clinical point of view, it is essential to eliminate cancer stem cells responsible for resistance and relapse. Our group and others have demonstrated that BMP molecules, members of the TGFβ superfamily, are key regulators of SCs and their niche in both normal and tumoral contexts. In order to analyze the role of the BMP pathway in the regulation of cancer stem cells (CSCs), we use two models: Chronic Myeloid Leukemia (CML) in a hematopoietic system which constitutes the standard model for the transformation of normal SCs and breast cancer in an epithelial system forming solid tumors, in which the existence of CSCs has been demonstrated but the origin of which remains unknown.

Our preliminary data indicate that, in these two CSC models, there is a deregulation in the BMP pathway. We hypothesized that, as is the case in glioblastoma, an alteration in the BMP signaling pathway and the cellular biological response in the blood and the breast is required to maintain the CSC phenotype and resistance. This could constitute a general mechanism of appearance of CSCs and resistance. We suggested that the deregulation of the BMP pathway could be due to different alterations linked to the various functions of the BMP family and may not necessarily be identical between the different tissues affected. We are testing this hypothesis in our models, using the molecular tools we have developed and are examining the effect of BMP deregulation on CSC appearance and properties such as quiescence, self-renewal, proliferation, differentiation, adhesion, migration, tumorigenic potential, and therapeutic resistance. We are particularly interested in the contribution of the microenvironment towards the maintenance of CSCs (such as the enzymatic function of CD10), resistance and escape from therapies. Lastly, we are currently exploring whether the links between BMP molecules and immune cells may contribute to the escape of CSCs from the immune response. This project is befitting of the wider aim of the lab to explore the role of CD10 and BMPs in the transformation of mammary SCs.

Our medium-term goals are to improve our understanding of the specific mechanisms governing the resistance of SCs and to develop a model system that allows the evaluation of novel targeted therapeutic strategies against SCs in the context of their environment.

PUBLICATIONS

 MAIN PUBLICATIONS  (2008-2018)                                                                                                                                                       (*Corresponding author; §: equal participation)

Voeltzel T*§, Flores-Violante M§, Zylbersztejn F, Lefort S, Billandon M, Jeanpierre S, Joly S, Fossard G, Milenkov M, Mazurier F, Nehme A, Belhabri A, Paubelle E, Thomas X, Michallet M, Louache F, Nicolini FE, Caron de Fromentel C, Maguer-Satta V*. (2018) A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome. Cell Death Dis. 9(10):1011. doi: 10.1038/s41419-018-1042-7. PMID: 30262802

 

Wu X, Kabalane H, Kahli M, Petryk N, Laperrousaz B, Jaszczyszyn Y, Drillon G, Nicolini FE, Perot G, Robert A, Fund C, Chibon F, Xia R, Wiels J, Argoul F, Maguer-Satta V, Arneodo A, Audit B, Hyrien O. (2018) Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions. Nucleic Acids Res 2;46(19):10157-10172. doi: 10.1093/nar/gky797. PMID: 30189101


Grockowiak E, Laperrousaz B, Jeanpierre S, Voeltzel T, Gobert S, Guyot B, Nicolini FE* and Maguer-Satta V*. (2017) Immature CML cells implement a BMP autocrine loop to escape TKI treatment. Blood. 130(26):2860-2871. doi: 10.1182/blood-2017-08-801019. PMID: 2913822


Bellanger A, Donini C, Vendrell J, Lavaud J, Machuca-Gayet I, Ruel M, Vollaire J, Grisard E, Győrffy B, Bièche I, Peyruchaud O, Coll JL, Treilleux I Maguer-Satta V, Josserand V and . Cohen P. (2017) The critical role of the ZNF217 oncogene in promoting breast cancer metastasis to the bone.. Journal of pathology. 242(1):73-89. doi: 10.1002/path.4882. PMID: 28207159


Clément F, Xu X, Donini C, Clement A, Omarjee S, Delay E, Treilleux I, Fervers B , Le Romancer M, Cohen P and Maguer-Satta V*. (2017) Long-term exposure to Bisphenol A or Benzo(a)pyrene alters the fate of human mammary epithelial stem cells in response to BMP2 and BMP4, by pre-activating BMP signalling. Cell Death Diff. 24(1):155-166. doi: 10.1038/cdd.2016.107. Epub 2016 Oct 14.PMID: 27740625


Laperrousaz B, Berguiga L, Nicolini FE, Martinez-Torres C, Arneodo A, Maguer-Satta V. Argoul F. (2016) Revealing stiffening and brittling of chronic myelogenous leukemia hematopoietic primary cells through their temporal response to shear stress. Phys Biol. 13(3):03LT01 doi: 10.1088/1478-3975/13/3/03LT01. PMID: 27254599 


Clement F, Zhu HH, Gao W-Q, Delay E and Maguer-Satta V*. (2015) Update of a Protocol to Quantify Epithelial Early Common Progenitors from Long-Term Primary or Cell Lines Sphere Culture. Curr Protoc Stem Cell Biol. 35:1E.7.1-8. PMID: 26544537


Nicolini FE, Etienne G, Dubruille V, Roy L, Huguet F, Legros L, Giraudier S, Coiteux V, Guerci-Bresler A, Lenain P, Cony-Makhoul P, Gardembas M, Hermet E, Rousselot P, Amé S, Gagnieu MC, Pivot C, Hayette S, Maguer-Satta V, Etienne M, Dulucq S, Rea D, Mahon FX. (2015) Nilotinib and pegylated interferon alfa 2a for newly diagnosed chronic phase chronic myeloid leukaemia patients. Results of a multicentric phase II study. Lancet Hematology, 2 (1): e37-e46. PMID: 26687426


Chapellier C,and Maguer-Satta V*. BMP2, a key to uncover luminal breast cancer origin linked to pollutant effects on epithelial stem cells niche. (2015) Molecular & Cellular Oncology. 3(3):e1026527. DOI: 10.1080/23723556.2015.1026527. PMID: 27314065


Chapellier C, Bachelard-Cascales E, Schmidt X, Clement F, Treilleux I, Delay E, Jammot A, Menetrier-Caux C, Pochon G, Besançon R, Voeltzel T, Caron de Fromentel, Caux C, Blay JY, Iggo R and Maguer-Satta V*. (2015) Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by over-amplifying BMPR1B cell response. Stem Cell Reports, 4(2):239-254. PMID: 25601208


Laperrousaz B, Jeanpierre S, Sagorny K, Voeltzel T, Ramas S, Kaniewski B, Ffrench M, Salesse S, Nicolini FE, Maguer-Satta V (2013). Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression. Blood 122(23): 3767-3777. PMID: 24100446


Nicolini FE, Ibrahim AR, Soverini S, Martinelli G, Müller MC, Hochhaus A, Dufva IH, Kim DW, Cortes J, Mauro MJ, Chuah C, Labussière H, Morisset S, Roche-Lestienne C, Lippert E, Hayette S, Peter S, Zhou W, Maguer-Satta V, Michallet M, Goldman J, Apperley JF, Mahon FX, Marin D, Etienne G. (2013) The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis. Haematologica. 98(10):1510-6. PMID:23716543


Bachelard-Cascales E, Chapellier M, Delay E and Maguer-Satta V*. (2012) A protocol to quantify Mammary Early Common Progenitors from long-term mammosphere culture. Curr Protoc Stem Cell Biol. Chapter 1:Unit 1E.7.PMID:22415837


Maguer-Satta V*, Chapellier M, Delay E and Bachelard-Cascales E. (2011) CD10: a tool to crack the role of stem cells in breast cancer. PNAS, 108(49):E1264. PMID:22109559

 

Maguer-Satta, V*. Besançon, R. and Bachelard-Cascales, E. (2011) Neutral endopeptidase (NEP/CD10): a multifaceted environment actor in stem cells, physiological mechanisms and cancer. Stem Cells. 29(3):389-96. doi: 10.1002/stem.592 ISBN 1066-5099, PMID:21425402


Cosset, E. Hamdan, G. Jeanpierre, S. Voeltzel, T. Sagorny, K. Hayette S. Mahon, F.-X Dumontet, C. Puisieux, A. Nicolini, F. E.and Maguer-Satta V*. (2011) Deregulation of TWIST-1 as a novel prognostic factor in chronic myeloid leukemia Blood. 3;117(5):1673-6. Epub 2010 Dec 1. ISBN, 0006-1971 PMID: 21123820


Bachelard-Cascales, E.. Chapellier, M. Delay, E. Pochon, G. Voeltzel, T. Puisieux, A. Caron de Fromentel C and Maguer-Satta. V*. (2010) The CD10-enzyme is a key player to identify and regulate Human mammary stem cells. Stem Cells 28,1081-88. PMID:20506111


Jeanpierre, S. Nicolini, FE. Kaniewski, B. Dumontet, C. Rimokh,  R. Puisieux, A. and Maguer-Satta, V*. (2008) BMP-4 mediates TPO effects on megakaryocytic differentiation in human primary cells. Blood.112, 3154-3163


Berger, M. Richard, C. Berger, J. Jeanpierre, S. Nicolini, FE. Tournilhac, O. Michallet, M. and Maguer-Satta, V*. (2008). Fludarabine chemotherapy alter cell-to-cell interactions in BM stem cell niche, likely involved in stem cell mobilization failure. Leukemia. 22(11):2131-4

 

 

 
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