The past decade has witnessed unprecedented progress in our understanding of the genetic changes underlying human pancreatic cancer. Led by a long series of important contributions by Program investigators, the genetic and epigenetic basis for pancreatic cancer has slowly been unraveled, with over 30 genetic loci now recognized to undergo mutation in this disease, and characteristic changes in gene expression reported for an even larger number of coding genes and non-coding microRNAs. However, the functional contribution of these mutations to the pancreatic cancer phenotype remains largely uninvestigated. The central Aim of this Program Project Grant is to narrow the gap between genetic and functional data, by determining the functional significance of molecular alterations identified in human pancreatic cancer. This functional annotation will be pursued by examining the impact of candidate dominant and recessive mutations, as well as characteristic changes in microRNA expression, using novel cell-, zebrafish- and mouse-based assays developed by members of our group. Four projects will be pursued: Project 1: Functional annotation of human pancreatic cancer genes in a zebrafish system (Leach);Project 2: Discovery and evaluation of prioritized mutations in human pancreatic cancer (Kern);Project 3: The Hippo signaling pathway in pancreatic cancer (Maitra);and Project 4: Functional evaluation of microRNAs in pancreatic neoplasia (Mendell). These projects will be supported by three shared Cores: Core A: Cellular and Transgenic Phenotyping Core (Huso);Core B: Zebrafish Core (Parsons), and Core C: Administrative Core (Leach). The investigators pursuing these projects are all leaders in the field of pancreatic cancer research, and have an outstanding track record of synergistic interaction. The Program also leverages many already existing resources available at Johns Hopkins, including aspects of the NCI Gl SPORE grant, core resources provided by the Johns Hopkins Comprehensive Cancer Center, and the independently funded Pancreatic Cancer Genome Project. Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications.

Public Health Relevance

Pancreatic cancer represents one of the most deadly human malignancies, with five year survival rates of less than 5% and no change in this figure over the past four decades. By determining the genetic basis for this disease, our program will generate clinically relevant information that is likely to directly impact on strategies for chemoprevention, early detection and treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S (J1))
Program Officer
Mietz, Judy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Park, J T; Johnson, N; Liu, S et al. (2015) Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey. Oncogene 34:2801-6
Rakheja, Dinesh; Chen, Kenneth S; Liu, Yangjian et al. (2014) Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat Commun 2:4802
Matthaei, Hanno; Wu, Jian; Dal Molin, Marco et al. (2014) GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "incipient IPMNs". Am J Surg Pathol 38:360-3
Chivukula, Raghu R; Shi, Guanglu; Acharya, Asha et al. (2014) An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration. Cell 157:1104-16
McAllister, Florencia; Bailey, Jennifer M; Alsina, Janivette et al. (2014) Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25:621-37
Bailey, Jennifer M; Alsina, Janivette; Rasheed, Zeshaan A et al. (2014) DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 146:245-56
Krzeszinski, Jing Y; Wei, Wei; Huynh, HoangDinh et al. (2014) miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature 512:431-5
Patel, Kalpesh; Kern, Scott E (2013) "Selective cell death mediated by small conditional RNAs" is not selective. Cancer Biol Ther 14:693-6
Streppel, Mirte Mayke; Pai, Shweta; Campbell, Nathaniel R et al. (2013) MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1. Clin Cancer Res 19:4067-78
Mendell, Joshua T; Olson, Eric N (2012) MicroRNAs in stress signaling and human disease. Cell 148:1172-87

Showing the most recent 10 out of 35 publications