PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Understanding the mechanisms that lead to the development and progression of PDA in order to identify novel methods of intervention is the greatest hope for prevention and treatment. Animal models have shown that the development of pancreatic cancer is driven by two events, the acquisition of an oncogenic mutation in KRas and pancreatic inflammation. Our previous work demonstrated that oncogenic KRas upregulates a soluble form of ICAM1 (sICAM1), which acts as chemoattractant for inflammatory macrophages (M1) to initiate the formation of pancreatic lesions. We also have shown that pancreatic lesions, by releasing IL-13, can crosstalk with M1 macrophage populations in order to induce their polarization to an alternatively-activated phenotype (M2) that is tumor promoting. This proposal focusses on understanding the mechanism of how macrophages are attracted by precancerous lesions, but also on how their conversion into tumor-associated macrophages can be prevented. It is our hypothesis that KRas-driven expression of ICAM-1 is a regulator of macrophage populations and its targeting can have major effects on development and progression of pancreatic cancer. To test this we will: determine how oncogenic KRas leads to formation of a soluble form of ICAM1 (Specific Aim 1); determine the roles of MMP3 and ICAM1 in attracting inflammatory macrophages (Specific Aim 2); To determine the in vivo function of MMP3 with respect to production of sICAM1, chemoattraction of macrophages and development of PDA (Specific Aim 3); and test an ICAM1 targeting strategy alone, and in combination with current chemotherapy or modulators of the tumor microenvironment (Specific Aim 4). Successful completion of our project will demonstrate the importance of KRas-induced expression and processing of ICAM1 for the development and progression of pancreatic cancer, but also lead to novel strategies to keep macrophages absent, and thus halt desmoplasia, lesion progression and metastasis.
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