TGFbeta-regulated epithelial-mesenchymal transition (EMT)

Abstract Aggressive tumors that are metastatic and intrinsically resistant to conventional therapies represent a critical issue mediating the morbidity and mortality of most, if not all tumors, including breast cancer. It is postulated that targeting the epithelial-mesenchymal transition (EMT) and the ensuing formation of cancer stem cells (CSCs) is likely to represent a means of reducing the rate at which primary breast cancers spawn metastatic derivatives. In the context of cancer, cells having undergone an EMT have enhanced tumor-initiating ability, are capable of generating mammospheres, exhibit cell-surface markers and gene expression profiles similar to both normal mammary (MaSC) and breast cancer (BCSC) stem cells and become more resistant to chemotherapeutics. We have recently demonstrated a role for TGFβ-induced EMT in the formation of tumor initiating cells (TICs), through a signaling pathway involving the RNA binding protein hnRNP E1 (E1). Herein, our data demonstrates that this TGFβ/E1/ signaling pathway leads to the induction of an embryonic lncRNA known as Platr18 (pluripotent associated transcript 18). We show that this lncRNA is not expressed in normal epithelium or other adult somatic tissues but is highly induced by the TGFβ/E1 axis and in cells having undergone an EMT or during cancer progression. The scientific premise of the proposal is that the TGFβ- mediated EMT program induces the generation of TICs and tumor progression through TGFβ/E1 signaling and reactivation of silenced Platr18. Its goals are to delineate the molecular mechanism(s) of Platr18 function and determine its role in modulating T-cell mediated immunity through VSIG-3 & tumor innervation through Sema4F.