Kinetic analysis of Myc-induced carcinogenesis in vivo

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DESCRIPTION (provided by applicant): Myc is a highly pleiotropic transcription factor that coordinates multiple, diverse aspects of cell proliferation and whose expression is frequently deregulated and/or elevated in human cancers. Our studies indicate that Myc orchestrates not only the wide variety of intracellular programs necessary for orderly cell expansion - cell metabolism, cell growth, cell cycle progression, de-differentiation and apoptosis - but also a suite of extracellular programs that reorganize the local somatic microenvironment and prepare it for the cell expanding in its midst. Oncogenic activation of Myc hijacks all of these diverse processes, allowing oncogenic Myc to instruct and maintain multiple aspects of the neoplastic phenotype. In this proposal, we will address three pivotal questions in Myc tumor biology. First, how does Myc activation in somatic cells in vivo instruct and maintain widespread tumorigenic changes in the immediate somatic microenvironment. Second, how is Myc oncogenic action determined by the cell/tissue type in which Myc is activated? Third, oncogenically activated Myc appears necessary for maintenance of tumors that it elicits. However, Myc is not itself mutated in most tumors but, instead, appears to act as an endogenous downstream conduit of proximal oncogenic lesions. To what extent is endogenous Myc activity required for tumor maintenance, and why? We will address these questions in three aims. In Aim 1 we will use our well-established and kinetically defined reversibly switchable pancreatic beta cell mouse model of Myc-induced tumorigenesis to ascertain how Myc precipitates the causal chain of events that reorganize the islet microenvironment. Focusing specifically on Myc-induced tumor angiogenesis, we will ascertain the role of inflammatory cytokines and infiltrating cells in initiating and maintaining tumor vasculature and the role this plays in tumor maintenance. In Aim 2 we will address the consequences of Myc action in multiple tissues using a novel transgenic mouse model that allows sporadic and reversible activation of Myc in any target tissue. Using this model, we will specifically focus on Myc oncogenic mechanism in lung. In Aim 3 we will use a novel mouse model in which we can reversibly inhibit endogenous Myc function in multiple tissues in vivo to determine the role played by endogenous Myc in maintenance of normal and neoplastic tissues. Relevance Myc is a pivotal regulator of cell growth that is aberrantly activated in many human cancers. Because it integrates so many diverse pathways necessary for tumorigenesis, it and its direct downstream agents are in principle attractive candidates for therapeutic targeting of many cancers. In this proposal we delineate how Myc exerts its multifarious tumorigenic effects in differing tissues and ascertain the extent to which Myc function is required to drive formation of cancers and, thereafter, maintain them.