Determinants of cellular pliancy
In human, the characterization of the early steps of tumorigenesis as well as the cellular context in which they arise is hindered by two inherent constraints: first, in most cancers, the cell-of-origin remains unknown, second, by the time a cancer is clinically detectable, it has already acquired multiple epigenetic and genetic hits, hampering the characterization of the early events involved in its genesis, as well as the cellular context in which these events occur. The de novo genesis of human breast cancers has recently been achieved in immunodeficient mice transplanted with uncultured human breast epithelial cell suspensions infected with viruses harboring activated cellular or viral oncogenes (PI3KCAH1047R, KRASG12V, SV40 early region) and/or mutant form of tumor suppressor genes (P53R175H). However, the full spectrum of normal mammary epithelial cells was not studied (i.e. from mammary stem cells to differentiated luminal cells), and the early cell behavior following oncogene activation was not analyzed, precluding the understanding of the role of the efficiency of state-specific cellular response to an oncogenic event in tumorigenesis. Our current work is built on the hypothesis that each discrete differentiation state of a cell cellular within a given lineage is associated with a unique efficiency response to oncogenic activation, which is epigenetically determined. We aim to provide a detailed and comprehensive characterization of the epigenetic determinants of the early cellular response in normal human mammary cells after an oncogenic activation and to investigate the possible use of innovative targeted therapeutics relying on their intrinsic metabolic and epigenetic characteristics.
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Meeting ID: 589 821 9756
Domain 4 - UMR 3666 / U1143 - Chemical Biology of Membranes and Therapeutic Delivery