Abstract EN:

Cell migration is crucial during morphogenesis and also in the adult where it participates in tissue renewal, immune response, wound healing as well as in cancer invasion and metastasis. In certain cases, cells move as individuals while some other processes require collective cell migration (Rorth 2012). In order to migrate collectively, cells need to establish and maintain a front-rear polarity axis, redistribute proteins in a polarised fashion and form cell-cell and cell-matrix interaction. Collective cell migration is crucial for many physiological processes, from embryonic development where it is involved in gastrulation and morphogenesis to the adult where it participates in wound healing, tissue renewal and immune responses. Many pathologies have been linked with aberrant collective cell migration, the first of all being cancer spreading (Rorth 2009, Friedl, Sahai et al. 2012, Te Boekhorst, Preziosi et al. 2016). During my PhD, I focused on the PTEN dependent mechanisms controlling collective cell migration. A wide number of genes are altered during oncogenesis including inactivation of tumour suppressors such as p53, p16 and retinoblastoma (Rb) and overexpression of gene encoding epidermal growth factor (EGF) (Tamura, Gu et al. 1999). PTEN is one such tumour suppressor gene which is frequently mutated or deleted in a wide range of human cancers, from glioblastomas to prostate, breast, kidney, lung, testes and thyroid cancers. In particular, PTEN`s function is altered in more than 60% of glioblastomas. It is altered mostly in high-grade invasive glioblastomas but not in low-grade gliomas suggesting an important correlation between PTEN absence and invasive properties of the cancer cells (Rasheed, Stenzel et al. 1997, Dey, Crosswell et al. 2008). In addition, PTEN is known to regulate several cellular functions including cell migration and lots of the mechanisms involved in single cell migration have been extensively studied (Davies, Gibbs et al. 1999, Iijima and Devreotes 2002, Gerisch, Schroth-Diez et al. 2012). Glioblastoma form the most common and lethal primary intracerebral tumours (Davis, Kupelian et al. 2001). Tumour spreading in the brain parenchyma is largely responsible for the resistance of gliomas to cancer treatment and yet no therapeutic treatment has been found to prevent tumour infiltration. The mechanisms by which cells invade the central nervous system have not yet been directly observed and for some aspects they still remain elusive (Davies, Gibbs et al. 1999). Glioblastoma can arise from astrocytes or their precursors and they have an incidence of approximately 5 cases per 100.000 inhabitants (Furnari, Fenton et al. 2007). Astrocytes are the main glial cells of the central nervous system. They participate in the regulation of brain homeostasis and in the formation of the blood-brain barrier (Kimelberg and Nedergaard 2010). Astrocyte migrate in a collective fashion during development (Gnanaguru, Bachay et al. 2013) and in the adult brain, they have been shown to undergo astrogliosis in response to inflammation or trauma. Here they are able to elongate, polarise and eventually migrate toward the site of interest in order to create a glial scar (Sofroniew 2014). For these many reasons, in the lab we use primary rat astrocyte as preferential model to study the mechanism of collective cell migration (Etienne-Manneville 2006) [...]