Centre de recherche en cancérologie - Lyon

The plasticity of cancer cells underlies their capacity to adapt to the numerous selective pressures they encounter from tumor initiation to metastatic spread. At the crux of this concept is the epithelial-mesenchymal transition (EMT). EMT is a latent embryonic transdifferentiation program that turns polarized epithelial cells into motile mesenchymal ones. In human cancers of epithelial origin, EMT commitment has primarily been implicated in cancer cell invasion and metastatic spread. Our observations further highlight the role of EMT-inducing transcription factors (EMT-TFs) of the TWIST and ZEB families in the initiation and the development of primary tumors, including neuroblastomas, breast cancers and melanomas. Consistent with this notion, we have shown that EMT commitment endows cancer cells with stemness properties and that EMT-TFs inhibit the p53- and Rb-dependent oncosuppressive pathways and cooperate with mitogenic oncoproteins to foster malignant transformation in vitro and in vivo. Their oncogenic functions are dependent on their modulatory role on cell differentiation, EMT-TFs displaying either oncosuppressive or oncogenic activities in neural-crest cell-derived melanocytes according to their impact on MITF-driven differentiation programs. Of utmost importance, EMT has been shown in vitro and in vivo to confer tumour aggressiveness and resistance to both conventional and targeted therapies. Targeting EMT-driven tumour cell plasticity may therefore represent an innovative approach for cancer therapy.

Recently, we have demonstrated that EMT-TFs are expressed in normal mammary stem cells and that their expression influences the entire natural history of breast tumourigenesis. Indeed, unlike differentiated cells, human mammary stem cells have the innate capacity to withstand an aberrant mitogenic activation. This property is based on an antioxidant program driven by ZEB1, a potent EMT-TF, and by the methionine sulfoxide reductase MSRB3, a ZEB1 transcriptional target. This pre-emptive program prevents the formation of oncogene-induced DNA damage, a major cause of genomic instability, and influences the emergence of cancer-associated events. Overall, these data suggest that malignant transformation of mammary stem cells does not hinge on genomic instability and indicate that intrinsic properties of the cell-of-origin dictate the genomic landscape of breast cancers. The aims of our team are: i) to characterize the oncogenic functions of EMT-TFs, ii) to decipher their respective roles in the early stages of tumorigenesis and their influence on the clonal dynamics of tumorigenesis, and iii) to determine the impact of their expression on resistance to anti-cancer therapies, including conventional chemotherapies, targeted therapies and immune therapies, with breast cancers and melanomas as priority tumor types. The ultimate objective is to design approaches promoting the blockade EMT-driven plasticity, with the goal to increase cancer cell sensitivity to anti-cancer therapeutics.

Subpopulations of normal mammary epithelial cells exhibit distinct early responses to an oncogenic event.
While differentiated cells undergo massive DNA damage, mammary stem cells can withstand aberrant mitogenic signaling through a pre-emptive program driven by ZEB1 and MSRB3. This specific behavior impacts the natural history of breast tumorigenesis by favoring malignant transformation in the absence of genomic instability (figure from Morel et al., Nat Med 2017).