MYC agisce da fattore di riprogrammazione tumorale tramite induzione di uno stato di staminalità cellulare in cellule epiteliali umane della ghiandola mammaria

Cancer is both a genetic and an epigenetic disease whose outcome is influenced by tumor microenvironment. These three determinants represent the major driving forces of tumorigenesis and cause the functional heterogeneity observed in most of the cancer types. Both normal and neoplastic cell populations are known to harbor subpopulations of Stem Cells (SCs) that can both self-renew and spawn more differentiated progeny that, in the case of cancer, forms the tumor bulk. For what concerns Cancer Stem Cells (CSCs), they are proposed to held most of the tumor initiating potential and a higher proportion of CSCs within a tumor often correlates with poorer prognosis. Accumulating evidences indicate that SCs transcriptional program of both normal and neoplastic tissues rely on common molecular regulators including important developmental signals, such as the WNT pathway, whose de-regulation is causative of tumor initiation. Given their importance in the maintenance and propagation of cancer, identifying the cell of origin of CSCs would represent a great opportunity for understanding the molecular mechanisms underlying the onset of tumorigenesis, thereby offering new therapeutic strategies. A likely scenario of how multistep tumorigenesis may proceeds is that pools of transit amplifying progenitor cells, that are mitotically more active and more numerous than SCs, may serve as targets of somatic and epigenetic alterations that would cause their de-differentiation, pushing them back to the SCs compartment. This emerging model is based upon recent findings that hierarchically organized cell populations are, at least in epithelial tissues such as the mammary gland, more plastic than previously imagined. In this view, cell transformation can be described as a cell reprogramming process toward a SC-like state, in which a committed cell has to over-come a number of epigenetic barriers, that normally stabilize it, in order to alter its identity. Although promising, the mechanisms that should drive to the epigenetic reprogramming of committed cells are largely undefined and the putative role of developmental signals in this process has not been elucidated so far. We hypothesize that the proto-oncogene c-MYC could represent a bona fide tumor reprogramming factor. c-MYC over-expression in cancer cells can result from constitutive activation of a number of developmental pathways that lay up-stream c-MYC expression, such as the WNT/β-Catenin pathway constitutive activation is a rate-limiting step in tumorigenesis. On the basis of the findings obtained in our laboratory, MYC is able to sustain embryonic stem cells self-renewal by activating the WNT/β-Catenin pathway, through direct recruitment of Polycomb Repressive Complex 2 (PRC2) on the promoter of the two major inhibitors DKK1 and SFRP1. We hypothesize that a similar mechanism could explain what happens in the early events of tumorigenesis. More specifically, MYC over-expression in committed cells could induce their reprogramming to a SC-like state, through induction of autocrine WNT pathway hyper-activation, therefore favoring the acquisition of further genetic and epigenetic insults, that would induce the uprising of a CSC phenotype. Our results indicate that MYC over-expression in human Immortalized Mammary Epithelial Cells (IMECs) induces a cellular reprogramming towards a luminal progenitor cell-like state and that such condition is associated to hyper-activation of the WNT/β-Catenin pathway. Unlikely wild type cells, MYC-enriched pool of progenitor cells is prone to originate CSCs, since an additional genetic insult, such as over-expression of PIK3CAH1047R, is sufficient to endow IMEC MYC with tumorigenic capacity, while has no effect on wild type cells.