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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]

Sara GorjestaniSolid 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.

PUBLICATIONS (resulting from this training):

None yet – trainee just recently appointed

Other publications (prior to Training Grant appointment):

Gorjestani S, Darnay BG, Lin X. TRAF6 and TAK1 play essential roles in C-type lectin receptor signaling in response to Candida albicans infection.
J Biol Chem. 2012 Nov 12. PMID: 23148225

Gorjestani S, Yu M, Tang B, Zhang D, Wang D, Lin X. Phospholipase Cγ2 (PLCγ2)  a key component in Dectin-2 signaling pathway, mediating anti-fungal innate immune ses. J Biol Chem. 2011 Dec23;286(51):43651-9. PMID: 22041900

Bi L, Gorjestani S, Wu W, Hsu YM, Zhu J, Ariizumi K, Lin X. CARD9 mediates Dectin-2-induced IKK ubiquitination leading to activation of NF-kappaB in response to the stimulation by the hyphal form of Candida albicans. J Biol Chem. 2010 Aug 20; 285(34): 25969-77. PMID: 20538615

Gorjestani S, Rider V, Kimler BF, Greenwell C, Abdou NI. Extracellular signal-regulated kinase 1/2 signaling in SLE T cells is influenced by oestrogen and disease activity. Lupus. 2008; 17(6): 548-54. PMID: 18539708