Fibro-inflammatory tumor stroma makes up the physical bulk of pancreatic cancer. Moreover, recent evidence suggests that far from being a passive component in pancreatic ductal epithelial neoplasia, stromal proliferation is crucial for tumor invasiveness and metastasis. The central cell in the pancreatic cancer associated tumor stroma is the activated pancreatic stellate cell (PSC). However, the cellular signals that drive PSC activation from their quiescent state, and hence drive stromal proliferation, are unknown. We postulate that pancreatic dendritic cells (DC) drive PSC activation and are responsible for stromal proliferation and the stepwise progression of pancreatic cancer. This hypothesis is based upon three recent disparate observations from our laboratories: (i) We reported that DC are potent activators of stellate cells in the liver after hepatic injury, (ii) DC expand more than 30-fold in the pancreata of LSL-KrasG12D mice with early PanIN lesions, (iii) DC adoptive transfer to the peri-pancreatic tissues of mice with existing pancreatic inflammation precipitates stromal desmoplasia and pancreatic ductal epithelia dysplasia. Our goal in Aim 1 is to establish a role for DC in pancreatic cancer. Our experimental plan is to initially define the temporal and spatial timeline for DC expansion in the pancreas during the stepwise progression from early pre-invasive lesions to advanced carcinoma in mice and humans. We will then show a cause and effect relationship between DC and pancreatic carcinogenesis using a DC depletion strategy in chimeric LSL-KrasG12D mice.
In Aim 2, using in vitro and in vivo modeling, we will establish DC activation of PSC as cellular mechanism for DC induction of stromal proliferation and tumor progression, and we will explore the cell signaling requirements for DC to effectively engage PSC. We expect our work to have considerable impact on both the understanding of pancreatic tumorgenesis and on novel therapeutics as targeting DC maybe an attractive means to modulate pancreatic cancer progression. Our proposal is highly innovative as it challenges the accepted role of DC as potent anti-tumor agents to one that is pro-tumorogenic by activating PSC and causing expansion of tumor stroma which has direct influence on tumor invasiveness. Our proposal also sheds new light on the 'inflammation-cancer'paradigm as this work will suggests that DC may be a central component in the sequence of inflammation leading to cancer by driving stromal expansion.
Pancreatic cancer is a devastating disease that is fatal in approximately 95% of cases. We postulate that dendritic cells which infiltrate pancreatic tumor are primary stimuli to pancreatic cancer progression by activating the tumor stroma. Our work will show that targeting dendritic cells in pancreatic cancer may be an attractive and novel approach to experimental therapeutics.
|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|
|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|
|Zambirinis, Constantinos P; Levie, Elliot; Nguy, Susanna et al. (2015) TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J Exp Med 212:2077-94|
|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|
|Zambirinis, Constantinos P; Ochi, Atsuo; Barilla, Rocky et al. (2013) Induction of TRIF- or MYD88-dependent pathways perturbs cell cycle regulation in pancreatic cancer. Cell Cycle 12:1153-4|
|Henning, Justin R; Graffeo, Christopher S; Rehman, Adeel et al. (2013) Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology 58:589-602|
|Court, Helen; Amoyel, Marc; Hackman, Michael et al. (2013) Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression. J Clin Invest 123:4681-94|
Showing the most recent 10 out of 17 publications