The 5 year survival rate for patients with pancreatic ductal adenocarcinoma (PDAC) has improved only marginally (3% ->6%) over the past 35 years and despite considerable effort to develop therapeutics to treat PDAC, there has been a failure to significantly shift patient outcome. What is required are new, innovative and complementary approaches that better define the biology that drives disease initiation and that sustains tumor formation and progression so that improved treatments can be developed. PDAC is thought to initiate in acinar cells that acquire an activating mutation in the Kras protooncogene and that subsequently transition to a duct- like state by a process known as acinar-ductal metaplasia (ADM). Although ADM is a common feature of pancreatic cancer patients, there remains a critical gap in defining the transcriptional networks that are triggered by Kras mutation and that control the ADM ->PDAC pathway. The long-term goals of this study are to define the biological pathways that initiate and maintain advanced disease. The objective is to identify the transcriptional changes that are induced upon Kras activation and to test their importance to tumor development. The central hypothesis is that PDAC initiates from acinar cells via a phenotypic switch that requires silencing the acinar transcription program and activating a ductal transcription program. This hypothesis will be tested by pursuing two Specific Aims - (1) to identify acinar transcription networks that prevent acinar ->PDAC progression and (2) to establish how the ductal SOX9 transcription network drives ADM/PDAC development. These complementary aims will be accomplished using gain-of-function and loss- of-function strategies in inducible PDAC mouse models and in 3D culture systems that mimic the in vivo ADM response. The central transcription events instrumental in KRAS-induced ADM will be rigorously tested in human PDAC cells and in primary patient samples. The rationale for the proposed research is that these studies will be the first to probe the initial transcriptional changes in KRAS-expressing acinar cells and the first to manipulate these pathways in PDAC tumors. This contribution is significant because it will (i) define the earliest regulatory points n KRAS-induced PDAC, (ii) identify downstream genes that are regulated by duct transcription networks, and (iii) test if perturbation of specific gene targets can influence tumor development. The proposed research is innovative because it represents a departure from the status quo by approaching the disease from the earliest transcriptional events that guide the conversion of acinar cells to ductal preneoplastic lesions and by following these transcriptional networks in pancreatic tumors. The discoveries made will define the primary biological events associated with PDAC (the fourth leading cause of cancer deaths in the U.S.) and will direct future approaches aimed at testing new biomarkers and developing improved diagnostic and therapeutic tools to successfully treat patients suffering from this deadly disease.
The proposed research is relevant to public health because discovery of the transcription pathways that drive pancreatic cancer will establish new avenues of investigation to treat patients prior to metastatic disease - a critical long-term goal that wil have the greatest net benefit to patient outcome. Thus, the proposed research is relevant to NCI's mission of fostering creative discoveries and innovative research strategies for protecting and improving health and reducing the burdens associated with cancer disease.
|Lee, Hoyoung; Kim, Yeji; Schweickert, Patrick G et al. (2014) A photo-degradable gene delivery system for enhanced nuclear gene transcription. Biomaterials 35:1040-9|
|Li, Zhiguo; Li, Jie; Bi, Pengpeng et al. (2014) Plk1 phosphorylation of PTEN causes a tumor-promoting metabolic state. Mol Cell Biol 34:3642-61|
|Shi, G; DiRenzo, D; Qu, C et al. (2013) Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene 32:1950-8|
|Song, Bing; Liu, X Shawn; Rice, Steven J et al. (2013) Plk1 phosphorylation of orc2 and hbo1 contributes to gemcitabine resistance in pancreatic cancer. Mol Cancer Ther 12:58-68|
|Direnzo, Daniel; Hess, David A; Damsz, Barbara et al. (2012) Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells. Gastroenterology 143:469-80|
|Godby, Richard C; Van Den Berg, Yascha W; Srinivasan, Ramprasad et al. (2012) Nonproteolytic properties of murine alternatively spliced tissue factor: implications for integrin-mediated signaling in murine models. Mol Med 18:771-9|
|Hess, David A; Humphrey, Sean E; Ishibashi, Jeff et al. (2011) Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice. Gastroenterology 141:1463-72|
|Gary, Dana J; Lee, Hoyoung; Sharma, Rahul et al. (2011) Influence of nano-carrier architecture on in vitro siRNA delivery performance and in vivo biodistribution: polyplexes vs micelleplexes. ACS Nano 5:3493-505|
|Garside, Victoria C; Kowalik, Agnes S; Johnson, Charis L et al. (2010) MIST1 regulates the pancreatic acinar cell expression of Atp2c2, the gene encoding secretory pathway calcium ATPase 2. Exp Cell Res 316:2859-70|
|Huh, Won Jae; Esen, Emel; Geahlen, Jessica H et al. (2010) XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum. Gastroenterology 139:2038-49|
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