The Cellular and Transgenic Phenotyping Core will provide a service-oriented resource along with ongoing technique development and optimization that will ensure the efficiency and productivity of project investigators in the functional evaluation of candidate pancreatic cancer sequences. This will be accomplished through the centralized and standardized use of both in vitro, cell based assays as well as detailed assessment of in vivo phenotypes in mouse, zebrafish, and xenograft models. The mouse is a well- characterized mammalian model system with an extensive genetic toolbox available for genetic manipulations to generate autochthonous tumors, immunodeficient strains that facilitate direct in vivo analysis of human cancer cells as xenografts, and a track record of relevance to human cancer biology and therapeutics. Zebrafish are an emerging cancer genetics model and developmental model that arecost efficient, permit high throughput in vivo vertebrate genetic screens, and can be efficiently analyzed due to their small size at maturity and optical clarity during development. Core A will provide centralized services for the efficient use and histological analysis of these models according to standardized criteria.
The Specific Aims are:
Aim 1) to provide histopathology interpretation, histological proliferation analysis, and gene pathway evaluation of mouse and zebrafish tissues supplied by Projects 1,2,3, and 4;
and Aim 2) to apply and refine ectopic and orthotopic xenograft models in immunodeficient mice for in vivo evaluation of the function of candidate pancreatic cancer sequences including genes or microRNA sequences using in vivo tumorigenicity, tumor growth, stromal development, and metastasis assays for Projects 2,3, and 4.
(Seeinstructions): Functional characterizationof the genes and microRNA'sinvolved in pancreatic cancer will lead to the discovery of new targets for treatment of pancreatic cancer which are desperately needed. The zebrafish and mouse models characterized in this proposal will in the future also serve as ideal tools for validation and safety testing of these new treatments before moving the new therapies into human clinical trials.
|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