As epithelial cells progress to carcinomas, increased autocrine TGF- signaling acquires a prominent role in cancer progression, by inducing an epithelial plasticity response that can lead to epithelial-mesenchymal transition (EMT). EMT results in cell de-adhesion and increased cell motility and invasion, a prerequisite of cancer cell dissemination, and is increasingly seen as an integral property of carcinoma stem cells. As TGF- signaling drives EMT, and TGF- responsiveness contributes to cancer progression, we have been studying the regulation of TGF- signaling, as it pertains to epithelial plasticity. The well-studied Smad signaling pathway regulates gene expression in response to TGF-, but the TGF-- induced epithelial plasticity response cannot be explained merely by changes in gene regulation. Accordingly, TGF--induced non-Smad signaling has received increasing appreciation. Supported by this grant, we have been studying the TGF--induced activation of the Erk MAPK and PI3K-Akt-mTOR pathways, and have started addressing their roles in EMT. The specific roles of TGF--induced activation of either pathway in the epithelial plasticity response remain to be further defined. We also found that cells regulate their responsiveness to TGF-, by regulating the TGF- receptor levels at the cell surface from intracellular stores. Increased glucose levels and insulin activate this upregulation of cell surfae TGF- receptors, which appears to be mediated by Akt activation and the Rab GTPase activating protein AS160, a direct target of Akt phosphorylation. We hypothesize that increased Akt activation, as commonly seen in carcinomas, or resulting from increased glucose or insulin stimulation, enhances the cell's TGF- responsiveness, and the sensitivity and susceptibility of cancer cells to EMT, and thus may promote cancer progression by enhancing TGF- responsiveness. We now seek to continue our research program aimed at characterizing the roles of non-Smad signaling mechanisms in the control of the cell surface TGF- receptor levels, and resulting TGF- responsiveness, and in TGF--induced EMT. We organized our current and future research in three Aims: (1) To study the effects of glucose or insulin on TGF- signaling, epithelial-mesenchymal transition, cancer stem cell generation and EMT-dependent cancer progression; (2) To define the molecular mechanisms regulating the cell surface presentation of the TGF- receptors in response to Akt activation; (3) To define the roles of TGF--induced Erk MAPK and PI3K-Akt pathway activation in epithelial-mesenchymal transition, and cancer stem cell generation. Our studies should provide novel mechanistic insights into the regulation of TGF- responsiveness and the roles of TGF--induced non-Smad signaling in the cellular TGF- response, in particular in EMT and cancer stem cell generation. These insights may link hyperglycemia or insulin treatment with cancer progression, through increased TGF- responsiveness, and reveal a new role for the increased Akt signaling that is commonly seen in carcinomas, thus contributing to cancer progression by enhancing TGF- responsiveness.
Most cancers derive from epithelial cells, i.e. those cells that line the surfaces of organs in our body. For these cancers, called carcinomas, to become deadly, they have to invade surrounding tissues and disseminate throughout the body, thus requiring the cells to behave more plastic and invasive than they normally do. Over the years, we have learned that the response of cancer cells to a secreted protein, named TGF-beta, is of key importance in rendering cancer cells invasive. We request a continuation of our research program that is aimed at understanding (1) the roles of signaling pathways that are activated by TGF-beta in the control of the invasive and plastic behavior of cancer cells, (2) the mechanisms that enhance the responsiveness of cells to TGF-beta, as seen in cancer cells, and in this way make the cells more susceptible to its activities.
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