Molecular Mechanisms of Tumor Cell Migration

At a glance

Death of cancer patients is often due to the spreading of cancer cells, that is the migration of cells from the primary tumor to secondary sites where they form metastasis. Our teams aims to better understand cell migration in the context of breast cancer and thus discover new therapeutic strategies to prevent metastasis.

Uncontrolled activation of receptor tyrosine kinases in cancer cells leads to excessive intracellular signaling and to the development of tumors. Overexpression of the receptor tyrosine kinase ErbB2 in mammary tumors is associated with aggressive and metastatic forms of the disease. Or team aims to a better understanding of the molecular mechanisms by which receptor tyrosine kinases such as ErbB2 control the cellular processes involved in cell migration and metastasis.

 

Overview

The activation of receptor tyrosine kinases initiates a multitude of intracellular signals. We have in particular identified a new effector of ErbB2 which is involved in cell migration, called Memo for Mediator of ErbB2-driven motility. Cell motility is a complex process which requires cytoskeleton remodeling and the formation of substrate adhesion complexes. While the role of the actin cytoskeleton has been widely studied, the role of microtubules remains poorly understood. Using live imaging techniques, we have shown that Memo controls microtubule capture at the leading edge of cells. Our recent work has shown that stabilization of microtubules at the leading edge is required for cellular chemotaxis.

Following on this study, we have then been able to unravel the mechanism by which Memo contributes to microtubule capture. This mechanism involves the formation of a complex with the RhoA GTPase and its effector mDia1. This module allows the recruitment of a microtubule capture complex formed of the tumor suppressor APC and of the ACF7 spectraplakin.

We have shown that the Memo/ACF7 pathway is part of a complex network which integrates a multitude of signaling pathways in order to control the dynamic properties of microtubules. This process involves microtubule capture by the concerted action of Memo and of the PLCϒ/PKC pathway, followed by their stabilization by e.g. the PI3K/Akt pathway.

We are currently studying the factors that control microtubule dynamics and cell migration, for instance by proteomics approaches focused on the identification of complexes involved in microtubule capture, in combination with imaging techniques which allow us to study the dynamics of these complexes in a cellular context.

A better understanding of the signaling networks involved in cell migration could allow the identification of new biomarkers so as to better understand disease progression, as well as the development of new therapeutic strategies aimed at preventing or at eradicating metastasis.

Figure 1:

Cell migration in response to ErbB2 activation by a heregulin gradient can be monitored by videomicroscopy in Dunn chambers. Each line corresponds to the track of one cell. Notably, migration is preferentially directed towards high concentrations of HRG (top).

Figure 2:

Expression of the fusion protein EB1-EGFP, a marker of microtubule (+) ends, in the tumor cell line SKBRr3 allows microtubule dynamics to be visualized. Each point corresponds to a (+) end, growing from organizing centers towards the cell periphery.

 

Main achievements

Our research over the last few years has focused on cellular signaling in particular in the context of breast cancer. We have notably demonstrated a new factor involved in ErbB2 signaling, the Memo protein, which we have shown to control microtubules and tumor cell migration. We have also elucidated the mode of action of this protein and characterized the corresponding new signaling pathway.

Following on this work, we now aim to characterize the complexes that control microtubule dynamics by systemics approaches and to assess their role in metastasis.

 

The team

Habib, Ali, Brice, Pascal, Danièle and Aurélie

 

Ali Badache :

PhD earned from Louis Pasteur University in Strasbourg (France) ; post-doctoral fellow at Loyola Unversity School of Medicine (Chicago) ; Research fellow at the Friedrich Miescher Institute for Biomedical Research (Basel, Switzerland).
Head of the ‘Molecular mechanisms of tumor cell migration’ group at the Centre de Recherche en Cancérologie de Marseille since 2005, (Avenir Inserm Award). Inserm Staff Scientist since 2005, Director of Research at Inserm since 2009. Habilitation to Supervise Research obtained in  October 2009.

Pascal Verdier-Pinnard :

PhD earned from Paul Sabatier University in Toulouse (1994) ; Habilitation to Supervise Research obtained in  2010 from Aix-Marseille University ; post-doctoral fellow at the National Cancer Institue (NCI), Bethesda (MD) ; Instructor then Assistant Professor at Albert Einstein College of Medicine (New York). Inserm Staff Scientist since 2006, first at CRO2 (Marseille) then at the CRCM since 2010.

Looking for PhD candidates: Imaging cytoskeletal filament organization at the molecular scale"

Looking for PhD candidates. Closing date April 10, 2017. "Imaging cytoskeletal filament organization at the molecular scale".

The project includes an internship in industry. Three-years-supported by the DOC2AMU program, Marie Skłodowska-Curie COFUND, A*MIDEX Foundation.

Cell division is a fundamental biological process that is essential for multiple aspects of animal physiology, including cell proliferation and differentiation, tissue growth and repair. Its dysfunction leads to several human pathologies, including tumour development and tissue degeneration. Cell division involves strong cell shape changes and thus heavily relies on the redistribution and cooperation of force-generating cytoskeletal filamentous proteins, notably actin filaments and microtubules. Little is known about the functional contribution of septins, a family of proteins which was recently recognized as a novel component of the animal cytoskeleton and which are essential for the successful completion of cell division. This project aims at developing optical and biological tools to decipher the organization of septins and their interaction with actin and microtubules during cell division. To this end, the student will implement dedicated optical imaging methods with the project co-supervisor at I. Fresnel with the goal to measure filament organization at high spatial resolution and potentially in real time. These measurements will be implemented using polarized fluorescence imaging, in which I. Fresnel has recognized expertise, on two systems: in vitro reconstituted cytoskeletal filaments from purified components, and dividing mammalian cells, with the cosupervisor at CRCM. In vitro studies will decipher the behaviour and local structure of single filaments and of filament assemblies, providing reference signatures for studies in cells. Functional studies in cells will then be performed at different stages of cell division. The molecular mechanisms at the origin of inter-filament organization will be investigated using septin mutants. The PhD student will work in co-supervision between Institut Fresnel (Doctoral School "Physics and Sciences of the Matter") and Centre de Recherche en Cancérologie de Marseille (CRCM) (Doctoral School "Health and Life Sciences"). The candidate is expected to be of biophysics background with knowledge in biology and a high interest in experimental optics. The work involving both optical instrumentation developments and biological sample preparation, the student will be involved in an interdisciplinary work where in vitro / cell sample developments, experimental imaging and data analysis will be equally important. A previous experience with interdisciplinarity during the master thesis is thus preferable, in particular involving optical microscopy. He/She should be motivated by the exploration of novel questions in biology. He/She should also be interested in the development of an instrument of interest for industry, since the detection device envisioned in this project can possibly lead to industrial development. The candidate will work for part of his/her time with an international collaborator and participate in several national and international conferences: he/she should therefore be capable of integration in international environments. To be eligible, the PhD candidate must not have resided or carried out their main activity (work, studies, etc.) in France for more than 12 months in the 3 years immediately prior to the start date (October 1st, 2017). For more information, please contact Sophie Brasselet (I. Fresnel) at sophie.brasselet@fresnel.fr or Pascal Verdier-Pinard (CRCM) at pascal.verdier-pinard@inserm.fr

Join the team "Molecular mechanisms of tumor cell migration"

Masters 1 & 2 and PhD

Masters 1 and Masters 2 students are welcome to join our team within the frame of the école doctorale des Sciences de la Vie et de la Santé of Aix-Marseille University. Students willing to pursue with a PhD thesis are invited to apply to the école doctorale for a fellowship.

PhD students can also directly apply to join the lab at the thesis level, provided they pass the entry exam of the école doctorale and obtain a grant.

Candidate post doctoral fellows are invited to contact the lab in order to write a proposal and submit a grant proposal.