Project 3 will use mouse models of multistage pancreatic carcinogenesis previously developed and[unreadable] concurrently analyzed by Project 1 to investigate the neoplastic microenvironment and its constituent cell[unreadable] types as functions of losses in the INK4a/Arf, p53, and/or SMAD4 tumor suppressors, and of activity of the[unreadable] PI3 Kinase pathway, all in the context of mutationally activated KRAS signaling. Microenvironmental[unreadable] parameters to be assessed include: angiogenesis and the character of the blood vasculature; the association[unreadable] of pericytes with the tumor vasculature; lymphangiogenesis and the morphology of the lymphatic[unreadable] vasculature; the abundance and types of infiltrating (tumor-enhancing) leucocytes and expression/activity of[unreadable] the matrix-degrading enzymes they produce; and the characteristics of the fibroblastic stromal cells.[unreadable] A central goal is to test the hypothesis that the angiogenic phenotype and other features of the neoplastic[unreadable] microenvironment of PanIN and PDAC are differentially regulated by the loss of particular tumor suppressor[unreadable] genes that are signatures of this disease. An ancillary goal, to be pursued in collaboration with Project 2, is[unreadable] to determine the importance of KRAS signaling via the PIS kinase network in the cancer cells for induction of[unreadable] the aberrant tumor microenvironment. Analysis of human tumor biopsies with the Experimental Pathology[unreadable] Core will assess the correlation of genetic and phenotypic parameters identified in the mouse.[unreadable] Neoplastic stage-specific preclinical trial designs will be established and used to test innovative[unreadable] chemotherapeutic regimens, targeted antiangiogenic therapies, and combinations that might guide future[unreadable] human clinical trials. Joint studies with the Imaging Core will develop probes that non-invasively visualize[unreadable] parameters of the microenvironment, both to monitor lesional progression, and responses to therapy.[unreadable] Biomarkers of the cell-of-origin/pancreatic cancer stem cell identified by Project 4 will be used to assess[unreadable] specific responses to therapy and roles in relapse/progression. .[unreadable] These studies, in engineered mouse models of de novo pancreatic cancer, will characterize in[unreadable] unprecedented detail the aberrant lesional microenvironment and its regulation by genetic mutations during[unreadable] multistage progression, and begin knowledge-based pre-clinical therapeutic trials with the potential to reveal[unreadable] strategies that could be translated into improved treatments for the human disease.