Pancreatic adenocarcinoma is distinct from most epithelial-based cancers in that the tumor mass is overwhelmingly composed of fibro-inflammatory stroma. The role of the pancreatic tumor stroma has recently risen in profile and has been shown to be essential for both tumor growth and invasiveness. Thus, targeting the stroma is an attractive approach to experimental therapeutics;however, the regulators of stromal expansion and the biochemical crosstalk between the inflammatory stromal compartment and the transformed epithelial compartment are poorly understood. In this proposal we will determine whether Toll-like receptor (TLR) ligation is a primary driver of stromal inflammation and epithelial mutagenesis in pancreatic carcinoma and elucidate the novel downstream signaling mechanisms and inflammatory cellular subsets that mediate its effects. We have found that the pancreatic cancer tumor microenvironment is rife with the byproducts of sterile inflammation that can act as ligands for TLRs. This observation - combined with our preliminary work demonstrating that TLRs are markedly upregulated on a diverse array of cells infiltrating human and murine pancreatic carcinomas - led us to postulate that TLR ligation drives stromal advancement. Moreover, we propose that TLR inhibition can potentially prevent or treat early pancreatic cancer by abrogating inflammatory desmoplasia.
In Aim 1 we will determine the relationship between clinico-pathologic features and outcome in human pancreatic cancer and TLR expression as well as determine whether the progression of human chronic pancreatitis to pancreatic cancer is correlated with TLR expression levels. We will also test the effects of TLR activation on pancreatic carcinogenesis in murine models.
In Aim 2 we will examine the effect of TLR inhibition on pancreatic tumorigenesis and determine whether TLR activation has direct mutagenic effects within the epithelial compartment in addition to promoting peri-tumoral fibro-inflammation.
In Aim 3 we will investigate the specific cellular and biochemical mediators of tumor progression downstream of TLR activation. We postulate the TLR ligation on peri-tumoral dendritic cells and macrophages leads to intense inflammation via canonical NF-?B and MAP-Kinase pathways. Our robust preliminary data further suggest that TLR-mediated inflammation in these cells provide IL-6 and other pro-inflammatory cytokines that promote STAT3 phosphorylation in the Kras-mutated epithelial cells leading to Notch activation in both epithelial and stromal compartments. This is the first investigation of a TLR-STAT3-Notch interface in pancreatic disease. Additionally, bolstered by preliminary data, we propose that this reciprocal activation loop promotes a distinctly aggressive oncogenic phenotype in the epithelial compartment, characterized by dysregulated expression of numerous cell cycle regulators (p16, p21, p27, p53, Cyclin B1, Cyclin D1) and oncogenic genes (c-myc, Rb, and SHPTP1). We believe that the experiments in this proposal will provide important insight into the regulation of peritumoral inflammation and stromal-epithelial cross-talk in pancreatic cancer and provide the scientific basis for the translation of our work to promising clinical trials utilizing clinical-grade TLR inhibitors.
Pancreatic cancer is a disease that carries an enormous human toll. The biochemical mediators responsible for pancreatic tumor progression are not well understood. We postulate that ligation of Toll-like receptors within the inflammatory tumor stroma drives both stromal advancement and epithelial mutagenesis and via novel signaling mechanisms. Our work will show that blockade of Toll-like receptors is a promising approach to experimental therapeutics in pancreatic carcinogenesis.
|Seifert, Lena; Werba, Gregor; Tiwari, Shaun et al. (2016) The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532:245-9|
|Greco, Stephanie H; Torres-Hernandez, Alejandro; Kalabin, Aleksandr et al. (2016) Mincle Signaling Promotes Con A Hepatitis. J Immunol 197:2816-27|
|Seifert, Lena; Werba, Gregor; Tiwari, Shaun et al. (2016) Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice. Gastroenterology 150:1659-1672.e5|
|Daley, Donnele; Zambirinis, Constantinos Pantelis; Seifert, Lena et al. (2016) Î³Î´ T Cells Support Pancreatic Oncogenesis by Restraining Î±Î² T Cell Activation. Cell 166:1485-1499.e15|
|Seifert, Lena; Miller, George (2016) Molecular Pathways: The Necrosome - A Target for Cancer Therapy. Clin Cancer Res :|
|Zambirinis, Constantinos P; Levie, Elliot; Nguy, Susanna et al. (2015) TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J Exp Med 212:2077-94|
|Seifert, Lena; Deutsch, Michael; Alothman, Sara et al. (2015) Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways. Cell Rep 13:1909-21|
|Deutsch, M; Graffeo, C S; Rokosh, R et al. (2015) Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis 6:e1759|
|Greco, Stephanie H; TomkÃ¶tter, Lena; Vahle, Anne-Kristin et al. (2015) TGF-Î² Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia. PLoS One 10:e0132786|
|Zambirinis, Constantinos P; Pushalkar, Smruti; Saxena, Deepak et al. (2014) Pancreatic cancer, inflammation, and microbiome. Cancer J 20:195-202|
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