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.

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.