Role of epigenetic mechanisms in cancer stem cells and tumor invasion.

Our group developed a model of mammary carcinogenesis based on the rat cancer stem cells LA7 [1]. LA7 when engrafted as a single cell in NOD-SCID mice, generate a primary tumor that contains self-renewing CSCs, differentiated cells and a progeny of elongated-fibroblast-like cells expressing EMT markers and recapitulate the entire process of tumor development, including invasion and metastasis [2]. The EMT process has been proposed as a preliminary event underlying the metastatic process, allowing tumor cells to acquire skills in migration and colonization of new tissues and organs [3]. Cell undergoing EMT loss apico-basal polarity, intercellular and cell-extra-cellular adhesions and expression of epithelial makers, gain fibroblast-like morphology and expression of fibroblast markers, reorganize the cytoskeleton and acquire cell motility and invasive behavior [3]. Evidence supports that stromal-cancer cell interaction and stromal factors contribute functionally to EMT of cancer cells. Since the elongated cells are rat cells, they are necessarily derived for the single rat cell that was injected, we therefore considered the generation of elongated cells an epigenomic event by which the LA7CSC changes their epigenomic program. To dissect the molecular pathways associated with EMT and their associated metastasis-promoting-function we performed microarray- and micro-RNA-array screening and a proteomic approach based on SILAC. We identified a set of genes linking the Wnt/?-catenin pathway and EMT process.