A mechanistic understanding of cancer rests heavily upon the mutated genes. These include genes causing familial tumor susceptibilities, governing replication fidelity, and residing in regulatory pathways. Pancreatic cancer is an unusually efficient system in which to identify distinctive mutational targets, discoveries to which our research group has contributed heavily. This success is due in part to highly informative structural patterns of homozygous deletions as well as a higher incidence of genome- maintenance mutations (especially those affecting homologous recombination) in this tumor type. Indications are that many recessive genes and perhaps additional dominant genes remain to be discovered in pancreatic cancer. Most of the high-risk pancreatic cancer families remain unexplained by known mutations, and most cancers having CIN (chromosomal instability) are not yet tied mechanistically to a molecular cause. Recessive mutations in novel genes, for example, are currently being discovered more rapidly than can be annotated for their functional significance. We recently explored and published key technical breakthroughs and special tumor cell resources that are newly available and can quickly accelerate this line of study. Powerful high-throughput sequencing techniques are underway to aid such studies, but will need to be complemented by a roadmap derived from a strategic structural analysis of the cancer genome such as we are developing.
Our specific aims will locate promising sites of new mutant genes. For genes having some existing functional clues, we can assess the effects of mutation using available assays. For truly novel genes having few clues as to their function, we can achieve missense mutations or gene disruption using technologies we developed for homologous recombination in somatic cells, with phenotypic assessment accomplished both by gene-specific assays and by orthotopic xenografting. For genes having unknown functional assignment and distant evolutionary conservation, a zebrafish model of gene impairment will be used to survey for developmental clues to function and for an ability to augment zebrafish pancreatic tumorigenesis. This latter technique seems surprising, but appears to offer immense efficiency for classifying novel genes. Our long-term goal is to provide a more complete foundation for future studies of familial susceptibility, disrupted signaling pathways, and genome instability in pancreatic cancer.

Public Health Relevance

(Seeinstructions): Pancreatic cancer is a genetic disease caused by mutations. We identified frequent mutations in the p16, SMAD4, BRCA2, and other genes, explaining the causes of many cases of familial forms of pancreatic cancer. We now need to efficiently survey large numbers of mutated genes arising through new technologies. These genes and techniques will be explored in this project

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA134292-02
Application #
8067012
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$300,431
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Hillion, Joelle; Roy, Sujayita; Heydarian, Mohammad et al. (2016) The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors. Gynecol Oncol 141:580-587
Choi, Eunyoung; Hendley, Audrey M; Bailey, Jennifer M et al. (2016) Expression of Activated Ras in Gastric Chief Cells of Mice Leads to the Full Spectrum of Metaplastic Lineage Transitions. Gastroenterology 150:918-30.e13
Hendley, Audrey M; Wang, Yue J; Polireddy, Kishore et al. (2016) p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia. Cancer Res 76:3351-63
Knabel, Matthew K; Ramachandran, Kalyani; Karhadkar, Sunil et al. (2015) Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice. PLoS One 10:e0124411
Pertea, Mihaela; Pertea, Geo M; Antonescu, Corina M et al. (2015) StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33:290-5
Hendley, Audrey M; Provost, Elayne; Bailey, Jennifer M et al. (2015) p120 Catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas. Dev Biol 399:41-53
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
Boj, Sylvia F; Hwang, Chang-Il; Baker, Lindsey A et al. (2015) Organoid models of human and mouse ductal pancreatic cancer. Cell 160:324-38
Roeser, J C; Leach, S D; McAllister, F (2015) Emerging strategies for cancer immunoprevention. Oncogene 34:6029-39
Chang, Tsung-Cheng; Pertea, Mihaela; Lee, Sungyul et al. (2015) Genome-wide annotation of microRNA primary transcript structures reveals novel regulatory mechanisms. Genome Res 25:1401-9

Showing the most recent 10 out of 65 publications