The mechanisms through which chronic injury and inflammation contribute to cancer are diverse and include effects on proliferation and differentiation of tumor cells themselves and on the stromal cell activities upon which tumor survival and spread depend. The proposed Program emphasizes two major themes that are common to all 3 projects and the scientific core. The first will address the molecular controls of cytokine and pattern recognition (PR) receptor mediated inflammatory function in the context of a newly discovered requirement for Epidermal Growth Factor Receptor (EGFR). This concept will have significant impact in mechanistic studies of cytokine and PR receptor signaling as well as in development and implementation of therapeutic strategy. EGFR function is required for signaling through multiple PR receptors (e.g., TLRs 3 and 9 and STING), gp130 linked receptors (IL6, OSM), and IL17 receptors, but that this linkage occurs in each case via novel, EGF ligand-independent mechanisms. The role of EGFR in multiple cancers is well established and it is the target for many therapeutics (e.g., trastuzumab, erlotinib, geftinib etc). Hence the consideration of how EGFR participates in inflammatory signaling in tumor cells, in myeloid and in other tumor stromal cell populations is likely to have substantial impact on the design and outcomes of therapies that target EGFR. The second theme will consider the distinct ways in which cytokine and PR receptors operate in different cell populations to link inflammatory activity with promotion of tumorigenesis. In the proposed Program, Project 1 (Sen) will focus on cytokine expression associated with EGFR-coupled signaling through TLR3, TLR9 and STING in myeloid cells while Project 2 will consider how EGFR signaling couples with cytokines utilizing GP130 (e.g., IL6, OSM) to modulate tumor cell behaviors that are STAT3 dependent. In Project 3 Dr. Li will consider how IL17 may use both EGFR-dependent and EGFR-independent signaling pathways in different cell populations (epidermal and stromal) to impact on different aspects of inflammation-associated tumor development and progression. Collectively these projects will test the following overarching hypothesis: that EGFR is a common mechanistic feature of signaling through a specific subset of cytokine and PR receptors that serves to regulate the magnitude and duration of diverse responses within the selection of cell populations that contribute in temporally and functionally distinct fashion to the multiple stages of carcinogenesis and tumor progression. The three projects outline experimental strategies to test this hypothesis through performance of the following common specific aims: 1. Define the molecular mechanisms involved in EGFR-dependent signaling from PRRs (TLR3/9 AND STING), GP130-linked cytokine receptors (IL6, OSM), and IL17R to control the magnitude and character of downstream responses that link with different mechanistic aspects of tumor progression. Emphasis will be on the basis for EGFR/cytokine/TLR interactions and the consequences of such interaction on distinct signals emanating from both EGFR and the cytokine/PR receptor. 2. Assess the distinct cell type specific contributions of EGFR/cytokine-PR receptor pathways using multiple models of inflammation-linked cancer development and progression.
The overall objective of the three projects and one scientific core that comprise this Program Project application is to define cellular and molecular mechanisms through which response to chronic injury and inflammation promote the development and progression of cancer. One central theme is to investigate how a signaling protein known to be important in many forms of cancer (Epidermal Growth Factor Receptor) integrates with multiple structurally distinct receptors for inflammatory signals within the tumor microenvironment to enable the tumor promoting outcome. The second important theme is definition of the cell type specific roles through which these signaling systems collectively enable and promote the development of cancer and how these are influenced by the inflammatory status of the individual.
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