CONTACT

Michelina PLATEROTI

Principal investigator

michelina.plateroti@univ-lyon1.fr

Centre Léon Bérard
Bât. Cheney D-1st floor
28 rue Laennec 
69373 LYON Cedex 08
FRANCE
FRAU Carla

Postdoctoral researcher
Carla.FRAU@lyon.unicancer.fr

GODART Matthias
UCHUYA CASTILLO Joel
AZNAR Nicolas
LE NEVE Clémentine
Voir les objectifs et projets Voir les publications

Collaborations

National
Drs F. Bertucci & E. Charaffe-Jauffret, Institut Paoli-Calmettes, Marseille.
Drs V. Cavaillès & P. Lassus, IRCM, Montpellier.
Pr J. De Mey, University of Strasbourg.
Dr P. de Santa Barbara, Inserm U1046 Montpellier.
Dr J.N. Freund, INSERM U682 Strasbourg.
Pr V. Laudet, Observatoire Océanologique de Banyuls-sur-mer.
Drs P. Mehlen & F. Lavial, CRCL, Lyon.
Dr B. Pain, Inserm U846, Lyon.

International
Pr A. Columbano, University of Cagliari, Italy.
Pr P. Galante, University Sao Paulo, Brasil.
Pr A. Moschetta, University of Bari, Italy.
Pr L.O. Penalva, University San Antonio, Texas, USA.
Dr D. B. Spicer, Main Medical Center Research Institute, USA

Founding

Foundation ARC
Ligue Contre le Cancer - départements du Rhône et de la Savoie
Institut National du Cancer

OBJECTIVES

Our team is studying the mechanisms that regulate gut stem cell (SC) homeostasis in physiological and pathological conditions. Gut SCs physiology depends on a complex interplay between the various cell types that constitute the stem cell niche and that interact via complementary signalling pathways including Wnt, Notch and BMP. A set of recent evidences has unquestionably demonstrated that the alteration of this crosstalk contributes to the neoplastic transformation of the intestinal SC and promotes tumor initiation.

Within this context, we are actively studying the cellular and molecular processes of gut SC transformation with the aim to develop novel therapeutic strategies. 

PROJECT

Context. 

Colorectal cancer (CRC) is one of the most common cancers in the world and the current therapeutic strategy includes surgical ablation and chemotherapy. However, the cancer reappears in 30-50% of cases. The peculiarity of the intestinal epithelium is its continuous renewal fuelled by multipotent stem cells (SC) located in the crypts, generating all differentiated cell types. Recent studies have highlighted that the crypt SC are the cells responsible for CRC. It is, in fact, proposed that their neoplastic transformation may be the cause of cancer stem cells (CSCs), known to support tumour growth, metastatic spread and responsible for drug resistance. In agreement with this hypothesis, a molecular signature of SCs is predictive of a high risk of recurrence in patients. Understand the mechanisms that control SC homeostasis and determine how their impairment contributes to the neoplastic transformation of these cells is needed to develop efficient diagnostic and therapeutic tools.

 In this context, we are developing several complementary research axes:

1. Signalling networks and physiopathology of the intestinal epithelial stem cells

Our team showed the involvement of thyroid hormones through the TRa1 nuclear receptor in regulating the homeostasis of the intestinal epithelium precursor cells in physiological and pathological conditions. These results opened new perspectives in the study of this extrinsic signal in the physiopathology of the crypt SCs.

We are currently investigating how this endocrine signal, by interaction with the Wnt and Notch pathways, is integrated in a complex network governing the intestinal development, stem cell homeostasis and carcinogenesis;

Focusing specifically on the intestinal SC, defined by the expression of the Lgr5 and Musashi1 markers, we analyse the importance of these same signalling networks in physiological and cancer stem cells.

2. Stress conditions and intestinal epithelium stem cells

The constitutive activation of the Wnt pathway is accompanied by the production of activated oxygen species (ROS), that are important actors of the neoplastic transformation of the crypt SCs. However, a sustained oxidative stress leads to a premature cell aging, suggesting the existence of mechanisms aimed to counteract their cytotoxic effects. We recently highlighted a new programme induced in the intestinal SCs in the pre-malignant lesions (dysplasia and adenomas) capable of ensuring the integrity of these cells under conditions of an oxidative stress induced by chronic inflammation or in response to the loss of function of the APC gene. Usually this programme is induced transiently but it remains active in a significant proportion of CRC. Several approaches are developed to study this process in detail:

Inducible knockout mouse models will allow to evaluate the importance of this programme in the regulation of SC homeostasis in physiological and pathological conditions. Inter-regulation between this programme and the network of TRα1/Notch/Wnt signalling pathways will be the subject of special attention;

We evaluate the selective advantage of CRC cells displaying the active programme;

We expand our analysis by examining the relevance of this programme in the initiation of other tumour types.

This project respond to the overall policy of the CLRC and the Centre Léon Bérard, to encourage the emergence of translational projects.

PUBLICATIONS

Selected publications

Cambuli FM, Correa BR, Rezza A, Burns SC, Qiao M, Uren PJ, Kress E, Boussouar A, Galante PA, Penalva LO, Plateroti M. A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness. Stem Cells, 2015. [Epub ahead of print] PMID: 26303183

Sirakov M, Boussouar A, Kress E, Frau C, Lone IN, Nadjar J, Angelov D, Plateroti M. The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine. Development, 2015. 142(16):2764-74. PMID: 26286942

Ozmadenci D, Féraud O, Markossian S, Kress E, Ducarouge B, Gibert B, Ge J, Durand I, Gadot N, Plateroti M, Bennaceur-Griscelli A, Scoazec JY, Gil J, Deng H, Bernet A, Mehlen P, Lavial F. Netrin -1 regulates somatic cell reprogramming and pluripotency maintenance. Nat Commun, 2015. 8;6:7398. PMID: 26154507

Lapierre M, Bonnet S, Bascoul-Mollevi C, Ait-Arsa I, Jalaguier S, Del-Rio M, Plateroti M, Roepman P, Ychou M, Pannequin J, Hollande F, Parker M, Cavailles V. The transcriptional coregulator RIP140 increases APC gene expression and controls intestinal homeostasis and tumorigenesis. J. Clin. Invest, 2014. 1;124(5):1899- 913. PMID: 24667635

J. Caramel, E. Papadogeorgakis, L. Hill, G.J. Browne, G. Richard, A. Wierinckx, G. Saldanha, P. Hutchinson, G. Tse, J. Lachuer, A. Puisieux, J.H. Pringle, S. Ansieau*, E. Tulchinsky*. A switch in the expression of embryonic transcription factors drives the development of malignant melanoma. Cancer Cell, 2013. 24: 466-480. PMID: 24075834

Cambuli FM, Rezza A, Nadjar J. and Plateroti M. Musashi1-eGFP mice, a new tool for differential isolation of the intestinal stem cell populations. Stem Cells, 2013. 31(10), 2273-8. PMID: 23712573

Diala I, Wagner N, Magdinier F, Shkreli M, Sirakov M, Bauwens S, Schluth-Bolard C, Simonet T, Renault VM, Ye J, Djerbi A, Pineau P, Choi J, Artandi S, Dejean A, Plateroti M. and Gilson E. Telomere protection and TRF2 expression are modulated by the canonical Wnt signaling pathway. EMBO Rep, 2013. 14(4), 356-63. PMID: 23429341

A-P Morel, GW Hinkal, C. Thomas, F. Fauvet, S. Courtois-Cox, A. Wierincks, M. Devouassoux-Shisheboran, I. Treilleux, A. Tissier, B. Gras, J. Pourchet, G. Browne, D.B. Spicer, J. Lachuer, S. Ansieau*, A. Puisieux*. EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS Genetics, 2012. 8 (5): e1002723 . PMID: 22654675

Rezza A, Skah S, Roche C, Nadjar J, Samarut J and Plateroti M. The overexpression of the putative gut stem cell marker Musashi1 induces tumorigenesis through Wnt and Notch activation. Journal of Cell Science, 2010. 123(Pt 19):3256-65. PMID: 20826465

Kowalik MA, Perra A, Pibiri M, Cocco MT, Samarut J, Plateroti M, Ledda-Columbano GM, Columbano A. TRa is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells. Journal of Hepathology, 2010. 53(4):686-92. PMID: 20638743

Kress E, Skah S, Sirakov M, Nadjar J, Gadot N, Scoazec JY, Samarut J and Plateroti M. Cooperation between the Thyroid hormone Receptor TRa1 and the WNT pathway in the induction of intestinal tumorigenesis. Gastroenterology, 2010. 138(5):1863-74. PMID: 20114049

Kress E, Rezza A, Nadjar J, Samarut J and Plateroti M. The Frizzled related sFRP2 gene is a target of the TR1 thyroid hormone receptor and activates the -catenin signaling in intestinal epithelial progenitors. J. Biol. Chem, 2009. 284: 1234-1241.

Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, Valsesia-Wittmann S, Caron de Fromentel C, Puisieux A. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell, 2008. 8;14(1):79-89. PMID: 18598946

Reviews invitées

Sirakov M., Kress E., Nadjar J., Plateroti M. The thyroid hormones and their nuclear receptors: new players in intestinal epithelium stem cell biology? Cell Mol Life Sci, 2014. 71(15), 2897-907. PMID: 24604390

Sirakov M, Plateroti M. The thyroid hormones and their nuclear receptors in the gut: from developmental biology to cancer. Biochim Biophys Acta, 2011. 1812(8):938-46. PMID: 21194566

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