We have found that the epidermal growth factor receptor (EGFR) is required to sustain activation of the oncogene STAT3 in response to IL-6 or oncostatin M (OSM), which signal through the common gp130 receptor. In the normal inflammatory response, the initial activation of STAT3 in response to IL-6 or OSM is soon down regulated by the STAT3-induced inhibitor SOCS3, a potent negative regulator of gp130 and JAK2. However, in cancer cells, STAT3 phosphorylation is re-established and sustained in a second wave of activation. A novel complex is formed, involving IL-6, IL-6 receptor, gp130, STAT3 and EGFR, in which Y1068 of EGFR, the known STAT3 docking site, is phosphorylated, thus facilitating the re-activation of STAT3 by a SOCS3-independent mechanism. We now seek to understand in detail how this second wave gp130-EGFR complex is formed and how it drives not only STAT3 phosphorylation, but also additional downstream signals that emanate from EGFR in response to activation by gp130 ligands. We also wish to investigate the functional importance of the second wave in cancers that rely heavily on the ability of gp130 ligands such as IL-6 and OSM to activate STAT3. In glioblastoma (GBM), we wish to understand the importance of EGFR in sustaining STAT3 activation through the mechanism we have identified. In breast cancer, we can now identify the gp130- EGFR interaction as an important contributor to an epithelial-mesenchymal transition (EMT) that is driven by OSM, leading to the acquisition of cancer stem cell (CSC) properties. Elevated OSM in the microenvironment is associated with increased risk of recurrence, while increased levels of OSM receptor on cancer cells are associated with poor outcomes. We hypothesize that prolonged STAT3 activation, facilitated by the gp130- EGFR interaction, is a key contributor to poor outcome in patients harboring tumors with elevated OSM.
In Aim 1, we will evaluate many details of the novel interaction between gp130 and EGFR. Which tyrosine residues of EGFR are phosphorylated in the second wave complex and which downstream pathways do they drive? Which proteins are present in the complex and what are the functions of each? Which genes are activated by prolonged phosphorylation of STAT3 in the second wave and how do the encoded proteins contribute to tumorigenesis and EMT? In Aim 2, the consequence of suppressing or activating the second wave on the ability of OSM to induce EMT, cancer stem cell expansion, and resistance to chemotherapy will be assessed.
In Aim 3, we will use syngeneic, orthotopic mouse models of triple-negative breast cancer and glioblastoma to determine the importance of how the presence of immune cells within the tumor microenvironment impacts the second wave and affects tumorigenesis in general. Our studies will significantly advance current understanding of how OSM and IL-6, derived from the tumor microenvironment, drive aberrant STAT3 and EGFR activation, leading to cancer progression and metastasis. Understanding these aspects should facilitate new therapeutic approaches aimed at suppressing this important signaling cascade.
STAT3 is a key oncogene that drives many properties of cancer cells. Normally, STAT3 is an important mediator of inflammation, helping us to resist infections. In normal cells STAT3 is quiescent. In response to infection or inflammation, it is activated transiently but soon returns to its basal state when the source of its activation is resolved. However, in cancer cells, STAT3 activation is constitutive, facilitating several different aspects of tumor survival and growth. We have discovered a novel mechanism for sustaining STAT3 activation in cancer, involving its interaction with the growth factor receptor EGFR, which is also up regulated in many cancers. We now seek to understand the details of how this interaction drives the expression of proteins that contribute to tumorigenesis. We find that the ability of EGFR to sustain STAT3 activation is an important contributor to the epithelial-mesenchymal transition, a process that leads to an increased ability of cancers to metastasize and to resist therapeutic drugs. This transition is facilitated by OSM, a protein that is secreted by immune cells within tumors. OSM drives prolonged STAT3 activation by means of an interaction between its receptor and EGFR and, consequently, high levels of OSM within tumors predict a poor outcome in patients. In Aim 1, we will evaluate many details of the novel interaction between the receptor for OSM and EGFR, including which proteins are expressed in response to STAT3 that is activated in this way and how these proteins function in tumorigenesis. In Aim 2, the consequence of suppressing the ability of OSM to activate STAT3 and induce EMT, metastasis, and resistance to chemotherapy will be assessed, using models of human breast cancer and glioblastoma, which are well known to depend heavily upon STAT3 activation, in immuno-compromised mice. In Aim 3, we will use mouse triple-negative breast cancers and glioblastomas in normal mice, to determine the importance of how OSM-secreting immune cells within the tumor impact the ability to sustain STAT3 activation and affect tumorigenesis in general. Our studies will significantly advance current understanding of how OSM drives aberrant STAT3 activation, leading thus to cancer progression and metastasis. This knowledge should facilitate new therapeutic approaches aimed at suppressing this important signaling cascade.
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