Concours d'attribution des Contrats Doctoraux 2017 - 2020

Les équipes « Polarité cellulaire, signalisation et cancer » dirigée par le Pr Jean-Paul Borg et «Biologie Structurale et Chimie-Biologie Intégrée» dirigée par les Drs Xavier Morelli/Yves Collette se focalisent sur l’identification et le ciblage de mécanismes moléculaires impliqués dans les cancers. Les deux équipes sont membres du Centre de Recherche en Cancérologie de Marseille (280 personnes, 19 équipes, 26 nationalités) installé au sein de l’Institut Paoli-Calmettes, un hôpital spécialisé dans la prise en charge des patients atteints de cancer, et à la Faculté de Pharmacie de Marseille.

Description du travail de recherche proposé au doctorant

Sujet de thèse proposé :

Titre    Ciblage du récepteur à tyrosine kinase PTK7 dans les cancers du sein

Malgré d’incontestables avancées thérapeutiques apparues au cours des dernières décennies, certains cancers du sein restent encore des défis médicaux et scientifiques. C’est le cas des cancers du sein triple négatifs appelés ainsi en raison de l’absence d’expression de HER2 et des récepteurs hormonaux, rendant les patientes inéligibles aux thérapeutiques ciblées. La recherche de cibles thérapeutiques dans ces cancers très agressifs reste donc une priorité.

L’équipe de Jean-Paul Borg a montré que le récepteur à tyrosine kinase PTK7 est surexprimé dans de nombreux cancers, dont les cancers du sein triple négatifs, et associé à un mauvais pronostic et au développement de métastases. Une caractéristique de PTK7 est l’absence d’activité catalytique de son domaine kinase, rendant inaccessible l’utilisation d’inhibiteurs kinases. PTK7 est par contre actuellement ciblé par un anticorps-médicament en phase précoce de développement clinique. Cette approche est intéressante mais n’éradique cependant pas PTK7 de la cellule tumorale.

Dans ce projet de thèse, les équipes se proposent de cibler PTK7 par une approche PROTAC (Proteolysis Targeting Chimera) récemment décrite capable de conduire à la dégradation de protéines d’intérêt par le protéasome. Cette technologie a démontré son efficacité pour éliminer des oncoprotéines dans des cellules tumorales (BCR-ABL dans les leucémies aigues myéloïdes). Grâce à un crible de chimiothèques développées par l’équipe de Xavier Morelli/Yves Collette spécialiste en biologie structurale et chimie, l’étudiant identifiera des composés chimiques bi-fonctionnels spécifiques de PTK7 et d’une E3 ubiquitine ligase capable de dégrader le récepteur. Ces composés seront ensuite testés in vitro et in vivo grâce à des modèles de cellules de cancer du sein développés au CRCM.

 

L'étudiant sera impliqué dans un programme interdisciplinaire de biologie-chimie développé en étroite collaboration avec les plateformes académiques (protéomique, conception de médicaments) et industrielles (découverte de médicaments IPC) mises en place au CRCM et à l'Institut Paoli-Calmettes.

Cell polarity, Signaling and Cancer

Figure 1 : Confocal imaging of cell-cell contact

At a glance

More than 90% of adult cancers arise from the malignant transformation of epithelial cells that normally shape organs such as breast and colon. Molecular events that alter the normal function of specific human genes, the so-called oncogenes and tumors suppressor genes, lead to impaired morphology and behavior of epithelial tissues that become tumoral and acquire novel functions such as the capacity to invade other tissues. Dissemination of cancer cells in the human body is a deadly event hardly tackled by the current therapeutic strategies. More research is therefore needed to explore new avenues able to prevent cancer dissemination.

Our multidisciplinary team studies the metastatic process at the tissue, cellular and molecular levels with the ultimate goal to identify novel therapeutic targets amenable to future treatments. We focus on solid tumors of epithelial origin such as breast and colon cancer, as well as on leukemia that, similarly to solid tumors, develop aggressive molecular characteristics.

Deciphering the basic mechanisms of epithelial differentiation is not only essential to understand normal physiology, but also crucial to improve our knowledge on the mechanisms of deregulation of cell adhesion, migration and polarity in cancers. We are currently pursuing the study of major playors of cell polarity at the organism, cellular and molecular levels, combining fundamental and transitional research in strong collaboration with clinicians, and a stimulating network of national and international collaborations.

Overview

Background

Genetic programs required for cell adhesion, cell migration, and cell polarity occurring during epithelial differentiation are driven by secreted ligands and receptors, as well as intracellular networks of signaling and architectural molecules. Deciphering the basic mechanisms of epithelial differentiation is not only essential to understand normal physiology, but importantly, it also improves our knowledge of how deregulation of these pathways leads to abnormal cell adhesion, migration and polarity - hallmarks of diseases such as cancers.

Some of the most prominent features of carcinoma are a higher resistance to apoptosis, a loss of the polarized cyto-architecture, and the acquisition of a motile phenotype. A large body of work has already revealed determinant molecules for the fate of epithelial cells and, in some cases, has shed light on their role in cancer. This is particularly the case for the study of components of cell polarity which has contributed important information on key proteins such as the tumor suppressors E-cadherin and LKB1, and more recently, the Scribble protein complex.

Our projects

When we started the lab ten years ago, we were the first to identify Erbin, a basolateral scaffold protein containing a PDZ domain, for its interaction with the ErbB2 tyrosine kinase receptor.

Since then, we have extended our interest to Erbin homologues, - Scribble and Lano -, and contributed to the characterization of these basolateral proteins in epithelial cells. For example, we first depicted biochemically and functionally the Scribble complex that comprises GEF and GAP proteins involved in cell migration. We are currently pursuing our investigations on Erbin and Scribble at the physiological and physiopathological levels using in vitro studies,- in particular state-of-the-art proteomics and functional cellular assays -, and mouse models.

We also recently became interested in the tumor suppressor LKB1 as well as in PTK7 and Vangl2, two cell polarity receptors genetically linked to Scribble. These receptors are known to participate in planar cell polarity (PCP) and are overexpressed in certain cancers.

We are currently studying the role of these polarity proteins in signal transduction and tumorigenicity.

From the beginning, our group has had a general interest in the discovery of new PDZ networks, especially when these are involved in cancer development and dissemination.  We recently cloned all PDZ domain sequences in C. elegans and human in collaboration with Jérôme Reboul. These resources are easily accessible for large screens to identify novel PDZ interactions by two hybrid in yeast and other systems, and represent a good start to unravel into the ‘PDZome’.

Overall, our fundamental research is done in strong collaboration with the clinical and biopathology departments of Institut Paoli-Calmettes, and is embedded in a very fruitful and stimulating network of national and international collaborations.

Figure 2 : Mass spectrometry analysis of protein complexes

About the team leader

Jean-Paul Borg

Eduction

  • Aix-Marseille University, PharmD | 1995
  • Aix-Marseille University, PhD | 1995
  • Howard Hughes Medical Institute, Post-doc| 1995-1998

Positions

  • 1995-1998 : Research Fellow, Howard Hughes Medical Institute, Ann Arbor, MI, USA
  • 1998-2006 : Senior Inserm Investigator, CRCM, Marseille, France
  • 2007-present : Scientific Director of Institut Paoli-Calmettes, Marseille, France
  • 2006-present : Professor of Cell Biology, Aix-Marseille University
  • 2012 : PU-PH, Director of CRCM

     

    Main achievements

    • First cloning of Erbin (ErbB2 interacting), a gene encoding a protein containing LRR and PDZ domains (Nat. Cell Biol. 2000)
    • First identification of a signaling complex ßPIX-GIT1 associated to the Scribble tumor suppressor (Curr Biol 2004)
    • In collaboration with Martin Schwartz’s team, first demonstration that LKB1 is an adherens junction-associated protein regulated by E-cadherin engagement (Curr Biol 2009)
    • First characterization of PTK7 overexpression in acute myeloid leukemia and correlation of this event to poor prognosis (Blood 2010)
    • First characterization of PTK7 implication in Wnt/ß-catenin canonical signaling (EMBO Reports 2011)
    • First purification of the endogenous Vangl1/Vangl2 heteromeric complex (PLoS One 2012)

    The team

    From left to right: Borg Jean-Paul, Sebbagh Michael, Axelle Garcia, Colombe Saillard, Wilfried Traore, Sebastien Martinez, Eric Bailly, Anne-Catherine Lhoumeau, Avais Daulat, Marie-Josée Santoni, Alexandre Drezet, Sylvie Marchetto, et Tania Guenneau-Puvirajesinghe.

    PhD fellowships in cell and cancer biology

    The Cancer Research Center of Marseille (CRCM), France is pleased to announce that two PhD fellowships will be available from 1 January 2017 or as soon as possible thereafter. The application deadline is November 30th 2016.

     

    Applications are invited for the three-year fellowship from applicants who hold or expect to hold a master´s degree in a field relevant to the following PhD projects: A. PDZ-mediated syndecan-phosphoinositide networks in trafficking and signaling; B. PDZ network associated with Vangl and Scribble cell polarity proteins and implication in cancer.

     

    Project description

    PDZ proteins co-evolved with multicellularity and control various aspects of receptor signaling and trafficking, both known to be deregulated during cancer progression. The two present projects aim to address how PDZ-supported networks impact on cell-cell communication (including via exosomes), and on cell polarity. This work should contribute our understanding of the role of PDZ-networks in physiology and systemic diseases like cancer.

     

    Project A aims at providing a comprehensive map of interactions between syndecans, PDZ domain proteins and phospholipids, and investigating their role in subcellular membrane trafficking, exosome secretion and the signaling of various receptors (in part with Systasy).

     

    Project B aims at elucidating the role of PDZ interactions of Vangl on the trafficking of the receptor and thereby to gain fundamental insight into how Vangl trafficking is involved in breast cancer. We expect to develop peptide inhibitors of the PDZ domains of Scribble and establish the functional consequences of inhibiting the Vangl-Scribble interaction in cancer models.

     

    These PhD fellowships are part of the EU-funded project, PDZnet, which is an ambitious inter- and multidisciplinary European Training Network under the H2020 Marie Skłodowska-Curie Actions (www.pdznet.eu) offering training for 14 PhD fellows. The PDZnet consortium contains 12 different partners in 6 EU countries (Denmark, Sweden, Germany, France, Italy, Portugal). The PDZnet training program involves a range of network wide training activities.

     

    Required qualifications

    The successful candidate must:

    ·         hold a Master´s degree in a relevant subject area prior to the starting date

    ·         be fluent in English and have excellent communication skills

     

    Preferred qualifications

    We are looking for a highly motivated individual with a background in molecular, biochemical, cellular and/or cancer biology, ideally with some experience in microscopy, cell fractionation and/or exosome purification.

     

    Supervisors

    Project A. Prof Pascale ZIMMERMANN, pascale.zimmermann(at)inserm(dot)fr, Team ”Spatio-temporal regulation of cell signaling”

    Project B. Prof Jean-paul BORG, jean-paul.borg(at)inserm(dot)fr, Team “Cell polarity, signaling and cancer”

     

    General job description

    Your key tasks as a PhD fellow at Cancer Center of Marseille are to:

    ·         manage and carry through your research project

    ·         take PhD courses

    ·         write scientific articles and your PhD thesis

    ·         participate in national and international congresses and scientific meetings

    ·         stay at an external research institution, preferably abroad

    ·         teach and disseminate your research

     

    Key criteria for the assessment of applicants

    ·         Professional qualifications relevant to the PhD programme

    ·         Relevant work experience

    ·         Previous publications

    ·         The grade point average achieved

    ·         Other professional activities

    ·         Language skills

    ·         The successful applicant is also required to be enterprising and to possess good interpersonal skills

     

    Formal requirements

    The position is available for a three-year period for applicants holding a relevant master´s degree.

     

    The candidate should have less than 4 years of research experience and must not have resided or carried out his/her main activity in France for more than 12 months during the last 3 years immediately prior to the recruitment.

     

    The successful applicant will be requested to formally apply for enrolment as a PhD student at Aix-Marseille University.

     

    The PhD student is expected to be affiliated to the graduate programme of Aix-Marseille University.

     

    Questions

    For further information, applicants may contact the supervisors Pascale Zimmerman and/or Jean-Paul Borg.

     

    How to apply

    Send CV, motivation letter and the coordinates of 2 referees by email to Pascale Zimmerman and/or Jean-Paul Borg.

    Deadline for applications: 30 November 2016.

    An answer as to the granting of the fellowship can be expected approx. 4 weeks after application deadline.

     

    The Cancer Research Center of Marseille wishes to encourage everyone interested in this post to apply, regardless of personal background.

    AMIDEX BIOCLOAK Project

    Tania Guenneau-Puvirajesinghe, a post doctoral fellow in Jean-Paul Borg's team, is the coordinator of an AMIDEX interdisciplinary project aiming to design a drug delivery system which can conceive a drug with concentric layers of graphene and pegylation, which provides a cloaking effect to prevent diffusion, and also physical barriers to vulnerable to enzymatic degradation and macrophage clean-up in the transporting environment of the bloodstream, thereby increasing the potency of the delivery drug molecule to the target site.

    http://www.puvirajesinghe.eu/