Molecular Mechanisms of Tumor Cell Migration

Dispersion of cancer cells, or cell migration, from the primary tumor to distal sites where metastases form is often the cause of death in cancer patients. The research in our group aims at a better understanding of this process, notably in the context of breast cancer, to enable the emergence of innovative therapeutic strategies targeting the formation of metastases.

At a glance…

The actin cytoskeleton is known as a main actor in cell migration. In contrast, the contribution of microtubules, another major cytoskeletal component, is still ill-defined. Our past research identified a signaling pathway that controls microtubule stabilization at the cell leading front and we demonstrated its key role in steering migration. Our present projects aim at identifying and characterizing, both at the structural and functional levels, protein complexes which control microtubule dynamic properties and thereby cell migration. More recently, we got interested in septins, a still poorly characterized cytoskeletal element that appears as a regulator of the oncogenic process, including cell migration; our research aims at determining how their ability to interact with actin filaments and /or microtubules contributes to their mode of action.

Through the study of mechanisms coordinating the organization of the cytoskeleton, actin filaments, microtubules and septins, we hope to unveil fundamental processes sustaining cancer cell motility, which could represent as many potential targets for future therapies.

La cellule en migration

More details…

An oncogenic signaling pathway regulating microtubules

Overexpression of the tyrosine receptor kinase ErbB2/HER2 in breast cancer is associated with aggressive forms of the disease. Our past research aimed at deciphering signaling pathways upon which ErbB2 promotes cancer cell migration and metastasis and at determining the specific role of microtubules. We had identified the protein Memo as a novel ErbB2 effector which controls microtubule capture at the leading edge of migrating cells, a process that appears to be required in response to chemotactic cues. Our research shows that Memo expression is associated with a poor prognosis and promotes lung metastases. Next, we demonstrated that its function implied the re-localization, via the RhoA GTPase and its effector, the mDia1 formin, of a microtubule capture complex harboring the tumor suppressor APC and the ACF7 spectraplakin, at the leading edge. APC and ACF7 belong to a family of proteins named +TIPs, which bind to the +end of microtubules via their interaction with EB1.

                     

Identification of complexes associated with EB1

In order to get insights into the mechanisms regulating microtubule dynamics during migration, we characterized the EB1 protein-protein interaction network by systematically performing a mass spectrometry analysis of associated proteins.

Notably, we identified a group of proteins previously linked to microtubule organizing centers. By molecular mapping and mass spectrometry analysis of the native complex, we found that EB1 binds to a specific isoform of myomegalin, SMYLE, to form a high MW complex with the AKAP9 scaffolding protein and the centrosomal protein, CDK5RAP2. SMYLE interacts also non-directly with the main microtubule nucleating complex, γ-TuRC. Inactivation of the SMYLE associated complex inhibits the nucleation and acetylation of microtubules, consequently altering microtubule capture and cell migration; but also astral microtubule formation and spindle orientation in mitotic cells during metaphase.

           Mode d'action potentiel du complexe associé à SMYLE (Bouguenina et al, PNAS 2018)

 

These results illustrate the fact that EB1-associated complexes can regulate microtubule dynamics at different levels: nucleation, growth and capture/anchoring of microtubules. In addition, they suggest that similar complexes may control microtubule function not only during migration but also during cell division and thereby contribute to different aspects of oncogenesis.

Work in progress

Our present research efforts pursue the characterization of other complexes regulating microtubule dynamics in migrating and dividing cells, both at the molecular and functional levels using proteomic/structural and cell imaging approaches, respectively.

Finally, microtubule function must be investigated with an integrative perspective, because it depends on the cellular context and on interactions with other cytoskeletal elements. Indeed, we revealed that isoforms of septin 9, usually considered a pro-oncogenic protein, while differentially interacting with actin filaments and microtubules, have opposite effects on cancer cell migration. We are pursuing this research by focusing on the molecular mechanisms underlying septin 9 actions on cell migration and its potential contribution to metastasis.

                                      septin et actin

The team

Habib, Ali, Brice, Pascal, Danièle and Aurélie


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.