Roles of PI3-Kinase Gamma and its Effectors in Inflammation, Immunosuppression and Fibrosis Associated with Pancreatic Cancer

Sara Gorjestani

Appointment Period: 2012-2013, Grant Years: [28]

Solid tumors are characterized by infiltration of two types of macrophages: pro-inflammatory macrophages that express interferons and activate T cells, and wound-healing macrophages that promote angiogenesis, immunosuppression and fibrosis. The number of wound healing macrophages in tumors vastly outnumbers the number of pro-inflammatory macrophages, thereby leading to tumor growth, metastasis and resistance to cancer therapeutics. Our studies have shown that myeloid cell PI3-kinase  activates integrin 41 to promote the trafficking of wound-healing monocytes to tumors (Cancer Cell 19, 715-727, 2011). This activation event leads to tumor angiogenesis, immunosuppression, collagen deposition and tumor growth and metastasis.  Blockade of PI3K gamma inhibits tumor inflammation and growth, indicating that mechanisms that promote myeloid cell trafficking can play important roles in tumor progression. In contrast, blockade of PI3K gamma does not affect the trafficking of proinflammatory monocytes. Thus, blockade of PI3K gamma and its effectors inhibit the trafficking of wound healing, tumor-promoting myeloid cells while permitting the trafficking of proinflammatory, tumor-inhibiting myeloid cells. The goal of this proposed research is to identify and target the molecular mechanisms by which tumor promoting monocytes are recruited to the tumor microenvironment. Specifically, we will test the hypothesis that a PI3Kgamma-BTKPLCgamma- RapGEF pathway is required to activate integrin 41 and promote the recruitment of tumor-promoting but not wound-healing monocytes to tumors. We will test the roles of PI3Kgamma, BTK, and PLC gamma isoforms 1 and 2, and Rap1 in the activation of myeloid cell integrin a4b1 in vitro using expression constructs, siRNAs and inhibitors. We will also evaluate the roles of these molecules in pancreatic tumor growth in vivo by orthotopically implanting LSL-KRasG12D/+; LSL-Trp53R172H/+; Pdx-1Cre pancreatic ductal carcinoma tumor cells in WT, PLCgamma and BTK knockout mouse models. Furthermore, we will test the effectiveness of PI3Kgamma, BTK and PLC gamma inhibitors on tumor inflammation and growth in the LSL-KRasG12D/+; LSL-Trp53R172H/+; Pdx-1Cre model of spontaneous pancreatic tumor growth.

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Other publications (prior to Training Grant appointment):