Centre de recherche en cancérologie - Lyon

The aim of our team consists of understanding how the aberrant activation of an embryonic transdifferentiation program, namely the epithelial-mesenchymal transition, frequently observed in human cancers, facilitates the tumour initiation. By studying the oncogenic properties of the key embryonic regulators and the cellular properties provided by EMT, we actually have demonstrated that EMT inducers and the associated transdifferentiation process affords cells an increased plasticity and an exacerbate sensitivity to micro-environmental changes, favouring thereby the escape of failsafe programs  and their malignant transformation. Deciphering the underlying mechanisms and developing strategies aimed at functionally neutralising these embryonic functions constitute our two main research axes.

The epithelial to mesenchymal transition (EMT) is a latent and reversible embryonic transdifferentiation process transiently providing epithelial cells with motility by converting them into mesenchymal ones. This program is regulated by a pleiad of signalling pathways that invariably converge to a limited number of transcription factors. Normally undetectable in a large majority of adult differentiated cells, these embryonic proteins are often aberrantly reactivated in cancers. As a reminiscence of their embryonic functions, by promoting EMT, they were found to promote cancer cell dissemination at the invasive fronts of tumours. We recently have demonstrated that they additionally alleviate the failsafe program induction (senescence and apoptosis) in response to oncogenic insults and thereby cooperate in vitro as well as in vivo with mitogenic proteins in promoting tumour development. The hijack of the embryonic process, likely through the associated  genetic reprogramming, also significantly accelerates cell transformation and dedifferentiation. These embryonic transcription factors therefore constitute key regulators of cell plasticity and important drivers of the neoplastic transformation.

Schematic representation of the interconnection between EMT and failsafe programs.
Reactivation of EMT-promoting embryonic transcription factors, induced in response to various stresses including hypoxia, mechanical constraints, and inflammatory responses, turns down the RB and p53 pathways. Through a positive feedback mechanism, EMT inducer expression is further enhanced, thus promoting EMT. Maintaining RB and p53 down-modulated is essential to generating a permissive environment for genetic and epigenetic reprogramming, providing cells with plasticity and adaptive properties. Unfortunately, these conditions constitute a favorable environment for tumor initiation.
Ansieau et al. Seminars in Cancer Biology 21: 392-397 (2011)

The aims of our team consist of:

- further exploring the oncogenic properties of EMT-inducers and the associated transdifferentiation program. We aim in particular to assess their impact on the cellular metabolism as well as on pathways regulating cell plasticity and determination.

- examining a potential oncogenic cooperation between EMT inducers and mitogenic oncoproteins in additional tumour progression models, thanks to transgenic mouse models.

- evaluating the therapeutic interest of targeting EMT-inducers or EMT.