Jean Paul THIERY

Molecular controls of Morphogenesis & Tumour Progression

Profile

Jean Paul THIERY

Principal Investigator Jean Paul THIERY
Jean Paul Thiery obtained his PhD from the University of Paris. He did his postdoctoral studies at the Rockefeller University, New York. In 1978, he established his research group at the Developmental Biology Institute of the CNRS in Paris. He became the head of a CNRS laboratory at the Ecole Normale Superieure in 1987 and joined the Institut Curie in 1995. His expertise was recognized by his appointment as the inaugural Director of the Department of Translational Research in Cancer at the Institut Curie in 2003. Professor Jean Paul Thiery joined IMCB in October 2006. From 16 April 2012, he is Head of the Department of Biochemistry, Yong Loo Lin School of Medicine at NUS as well as Research Director at IMCB.

Molecular controls of morphogenesis and tumour progression

The epithelial cell has a strictly defined shape and polarity in contrast to the potentially migratory mesenchymal cell. Many critical developmental processes involve the transition and interaction between epithelial and mesenchymal cells, processes which may be recapitulated in cancer. Growth factors and adhesion molecules are key regulators of embryonic development, playing a major role in signal transduction pathways governing fundamental aspects of cell function, shape and polarity.

Although signal transduction pathways controlling histogenesis are highly complex, they must be unravelled to understand the basic principles of morphogenesis. Activation of signal transduction pathways may also regulate stem/progenitor cell morphogenesis and tumour progression. Therefore our ultimate goal is to identify critical nodes in signal transduction pathways pivotal to development and cancer that may also provide new therapeutic targets.
Our laboratory combines biophysical approaches and advanced imaging techniques to study the mechanochemistry of cell-cell and cell-substrate adhesion (Click here to see more...). A dual pipette assay has been modified to measure the force required to separate cell doublets expressing different levels of type I or type II-cadherins (Fig. 1). Our studies indicate that initial adhesion not exceeding several nano-Newtons is reinforced only following cortical actin polymerization. Type II cadherin-7 and -11 is significantly less adhesive than E- and N-cadherin. These findings suggest that in vivo, cadherin-7 and -11 mediates transient adhesion, favouring motility and invasion, while E- and N-cadherin mediates stable adhesive contacts. Crosstalk mechanisms regulating the adhesive strength of cell-cell and cell-substrate adhesion are also being analysed using cell lines that undergo reversible epithelial–mesenchymal transition (EMT). We are currently developing transcriptomic and proteomic approaches to investigate the respective contribution of tyrosine kinase and phosphatase receptor signalling to EMT.
Other approaches are also being used in our laboratory to investigate EMT. Studies of in vivo cell adhesion and migration have benefited from the establishment of a transgenic mouse line driving the expression of transgenes in migratory neural crest cells following lineage specification (Fig. 2). The murine mammary gland is being used as a model to identify the molecular mechanisms governing induction, growth and branching morphogenesis (Fig. 3). Distinct signalling pathways including FGF10/FGFR2b, Wnt and Gli3 are active during the initial phase of mammary placode development. However, each placode is characterized by a unique molecular code established at initiation of induction. Our studies using a number of transgenic lines aim to further define this molecular code (Click here to see more...). The laboratory has characterized a murine breast stem progenitor cell that exhibits a basal phenotype. Targeting of an activated form of b-catenin in the basal layer of the developing mammary gland induces focal hyperplasia. These hyperplastic nodules develop in situ and invasive breast carcinomas of the basal phenotype. Using this tumour model we aim to identify tumour suppressors and oncogenes involved in oncogenesis of the basal carcinoma subtype. In parallel, the laboratory will pursue oncogenomic studies on human breast carcinoma with the basal phenotype.

Research

Research

Group Photo of JPT lab

Optics and bioinformatics


Optics and bioinformatics
State-of-the-art optical, image analysis, and bioinformatics approaches are being used to quantitatively describe biological processes involved in cell adhesion, epithelial-mesenchymal transition, tissue morphogenesis and tumour progression. These approaches utilise instrumentation development , image analysis, high throughput screening and bioinformatics techniques.

Real time imaging

We are using the most advanced optical microscopy techniques to study real-time dynamics of major cellular processes including intracellular trafficking, adhesion, motility and generalised cell behaviour. Our multi-modality microscope system combines the following functions:
  • Nikon wide-field inverted video-microscope
  • Piezo-driven 3D-imaging software with point spread function based deconvolution facility
  • Rapid FRAP (fluorescent recovery after photo-bleaching) and PA (photo-activation) system for induced photo-bleaching or photo-activation of appropriately tagged proteins at precise cellular locations or on specific organelles
  • TIRF (total internal reflection fluorescence) to study real-time membrane dynamics
  • Dual View system to separate the signal of two simultaneously emitting fluorophores

Contacts: Yeh-Shiu Chu, Eva Tomaskovic-Crook, Victor Racine

Mechanochemistry of cell adhesion
Micropipette force probes for studies of cell-cell and cell-substrate adhesion (pipette assay)


  • Development of substrate patterning by micro-contact printing technologies to investigate contact adhesion

Contacts: Yeh-Shiu Chu, Kelvin Kian Ngiap Chua

Image analysis
Image analysis aims to extract quantitative information to describe fluorescence distribution, cell morphology and dynamics. Analyses must be reproducible, user-independent and can perform large scale sampling without tedious work. Our main analyses include:

  • FRAP recovery quantification
  • Would healing measurement
  • Fluorescence colocalization analysis
  • Fluorescence and phase contrast segmentation
  • Cell morphometry
  • Cell / object tracking
  • High content image analysis



In collaboration with Frederic Bard Group

Contact: Victor Racine

Bioinformatics
Our current work focuses on gene expression data of breast cancer samples and cell lines. A principal aim of this approach is to discover relevant pathways in the basal phenotype.
In collaboration with Prof Alan Porter we are using computer-aided drug discovery programs to discover new therapeutic molecules to target breast cancer.

We are also in collaboration with Frederic Bard Group to support bioinformatic aspects of high content screening experiments such as:

  • Cell segmentation
  • Morphometric cell features extraction
  • Feature normalization
  • Feature selection
  • SVM classification
  • Hierarchical clustering

Contact: Agnes Tan, Victor Racine

Staff

Department: Jean Paul THIERY

Name: Weimiao YU

Designation: Senior Research Fellow

Email: wmyu@imcb.a-star.edu.sg


Name: Kian Chung LEE

Designation: Manager

Email: kclee@imcb.a-star.edu.sg


Name: Jill Mae Lan THAM

Designation: Research Fellow

Email: mcbthamj@imcb.a-star.edu.sg


Name: Sayantani NANDI

Designation: Research Officer

Email: nandis@imcb.a-star.edu.sg


Publications

Publications

Mechanochemistry of cell adhesion

Théry M, Jiménez-Dalmaroni A, Racine V, Bornens M, Jülicher F.
Experimental and theoretical study of mitotic spindle orientation.
Nature. 447:493-6, 2007.

Cuvelier D, Théry M, Chu YS, Dufour S, Thiéry JP, Bornens M, Nassoy P, Mahadevan L
The universal dynamics of cell spreading,
Current Biology, 17:1-6, 2007.
 
Chu YS, Eder O, Thomas WA, Simcha I, Pincet F, Ben-Ze’ev A, Perez E, Thiery JP, Dufour S
Prototypical Type-I E-cadherin and Type-II cadherin-7 mediate very distinct adhesiveness through their extracellular domain. J. Biol. Chem. 281:2901-10, 2006.

Théry M, Racine V, Pépin A, Piel M, Chen Y, Sibarita JB, Bornens M.
The extracellular matrix guides the orientation of the cell division axis.
Nat Cell Biol. 7:947-53, 2005.

Chu YS, Dufour S, Thiery JP, Perez E, Pincet F
Johnson-Kendall-Roberts theory applied to living cells.
Phys. Rev. Lett. 94:028102, 2005

Chu YS, Thomas WA, Eder O, Pincet F, Perez E, Thiery JP, Dufour S
Force measurements in E-cadherin-mediated cell doublets reveal rapid adhesion strengthened by actin cytoskeleton remodeling through Rac and Cdc42.
J. Cell Biol. 167:1183-94, 2004

Epithelial mesenchymal Transition

J.P. Thiery and J. Sleeman.
Complex networks orchestrate epithelial-mesenchymaltransitions.
Nat. Rev. Mol. Cell Biol. 7 : 131-142, 2006.

Breast cancer oncogenomics

Bollet MA, Servant N, Neuvial P, Decraene C, Lebigot I, Meyniel JP, De Rycke Y, Savignoni A, Rigaill G, Hupé P, Fourquet A, Sigal-Zafrani B, Barillot E, Thiery JP.
High-resolution mapping of DNA breakpoints to define true recurrences among ipsilateral breast cancers.
J Natl Cancer Inst.
100:48-58, 2008.

Stransky N, Vallot C, Reyal F, Bernard-Pierrot I, de Medina SG, Segraves R, de Rycke Y, Elvin P, Cassidy A, Spraggon C, Graham A, Southgate J, Asselain B, Allory Y, Abbou CC, Albertson DG, Thiery JP, Chopin DK, Pinkel D, Radvanyi F.
Regional copy number-independent deregulation of transcription in cancer.
Nat Genet.
38:1386-96, 2006.

Breast cancer micrometastases

Vincent-Salomon A., Pierga J.Y., Couturier J., d’Enghien C.D.,  Nos C., Sigal-Zafrani B., Lae M., Freneaux P., Dieras V., Thiery J.P. and  Sastre-Garau X.
HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases; a possible tool  for anti HER2 therapy management?
Br. J. Cancer 96: 654-659, 2007.

Braun S., Vogl F., Naume B., Janni W., Osborne M. P., Coombes R. C., Schlimok G, Diel I. J., Gerber B., Gebauer G, Pierga.J-Y., Marth C, Oruzio D., Wiedswang G, Solomayer, E-F., Kundt G., Strobl B., Fehm T., Wong G. Y. C., Bliss J., Vincent-Salomon A., and Pantel, K. for the Pooled Analysis Study
Pooled Analysis Study Group (additional contributors) : Wischnik A., Mueller P., Steinfeld D., Schulz C., Borgen E, Kåresen R, Nesland J M., Kvalheim G., Friese K., Krause A., Sommer H. L., Rack B., Jaeger W., Potter C., Mansi J. L., Homewood J., Magdalénat H., J-P. Thiery.
International Pooled Analysis of Prognostic Significance of Bone Marrow Micrometastasis in Patients with Stage I, II, or III Breast Cancer.
New England  J. Med. 353:793-802, 2005.

Neural crest cells

M. Breau, M. Eder, O. Blanche, C. Brakebush, R. Fassler, J.P. Thiery and S. Dufour.
Removal of b1 integrin in the enteric neural crest lead to a Hirschprung disease
Development 133: 1725-1734, 2006.

Broders-Bondon F.,  Cheneau A., Romero-Oliva F.,  Mayor R Mazabraud A. and Thiery JP.
Regulation of Xsnail2 expression by RhoGTPases.
Dev. Dyn. 236: 2555-2566, 2007.

Modeling breast cancer basal phenotype

J. Teulière, M.M. Faraldo, M-A. Deugnier, M. Shtutman, A. Ben Ze’ev, J.P. Thiery and M.A. Glukhova 
Targeted activation of beta-catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia.
Development 132: 267-277, 2005.

Imaging  in cell biology

Moutsimilli L, Farley S, El Khoury MA, Chamot C, Sibarita JB, Racine V, El Mestikawy S, Mathieu F, Dumas S, Giros B, Tzavara ET.
Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways. Neuropharmacology, 2007.

Racine V, Sachse M, Salamero J, Fraisier V, Trubuil A, Sibarita JB.
Visualization and quantification of vesicle trafficking on a three-dimensional cytoskeleton network in living cells.
J Microsc. 225:214-28, 2007.

Bioengineering

Chua KN, Lim WS, Zhang P, Lu H, Wen J, Ramakrishna S, Leong KW, Mao HQ.
Stable immobilization of rat hepatocyte spheroids on galactosylated nanofiber scaffold.
Biomaterials
26:2537-2547, 2005.

Lu HF, Chua KN, Zhang PC, Lim WS, Ramakrishna S, Leong KW, Mao HQ.
Three-dimensional co-culture of rat hepatocyte spheroids and NIH/3T3 fibroblasts enhances hepatocyte functional maintenance.
Acta Biomaterialia 1:399-410, 2005.

Emma Luong-Van ,  Lisbeth Grøndahl ,  Kian Ngiap Chua ,  Kam W Leong ,  Victor Nurcombe ,  Simon M Cool
Controlled release of heparin from poly(epsilon-caprolactone) electrospun fibers.
Biomaterials 27:2042-2050, 2006.

Kian-Ngiap Chua, b, Chou Chai, Peng-Chou Lee, Yen-Ni Tang, Seeram Ramakrishna, Kam W. Leong and Hai-Quan Mao
Surface-aminated electrospun nanofibers enhance adhesion and expansion of human umbilical cord blood hematopoietic stem/progenitor cells.
Biomaterials 27:6043-6051, 2006.

Kian-Ngiap Chua, Yen-Ni Tang, Chai-Hoon Quek, Seeram Ramakrishna, Kam W. Leong and Hai-Quan Mao
Dual-functional fibrous scaffold enhances P450 activity of cultured primary rat hepatocytes.
Acta Biomaterialia
3:643-650, 2007.

K. Chua, C. Chai, P. Lee, S. Ramakrishna, K. Leong, H. Mao
Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells.
Experimental Hematology 35:771-781, 2007.

Kenneth Lin, Kian-Ngiap Chua, Gregory T. Christopherson, Shawn Lim and Hai-Quan Mao
Reducing electrospun nanofiber diameter and variability using cationic amphiphiles.
Polymer 48:6384-6394, 2007.