Recipient Organization
UNIVERSITY OF NEVADA
(N/A)
RENO,NV 89557
Performing Department
(N/A)
Non Technical Summary
Pancreatic cancer is often diagnosed at an advanced stage and it is highly resistant to conventional chemotherapy and radiation therapy which makes it difficult to treat. The progression from normal pancreatic epithelium to pancreatic cancer is associated with the accumulation of several genetic mutations and gradually evolves via precursor lesions, called pancreatic intraepithelial neoplasia (PanIN) lesions. Epidemiological studies have suggested that consumption of cruciferous vegetables is associated with a lower risk of developing cancers, including pancreatic cancer.The overarching goal of this project is to characterize the efficacy of oral administration of the cruciferous vegetable watercress (Nasturtium officinale) on preventing the development and progression of early lesions of pancreatic intraepithelial neoplasia to more advanced lesions and pancreatic cancer, and on modulating the gut microbiome. The specific aims of this project are (1) to determine the efficacy of freeze-dried watercress on preventing the development and progression of precursor PanIN lesions to invasive pancreatic adenocarcinoma, by using a transgenic animal model which resembles histopathological features of the human disease, and (2) to characterize the effect of freeze-dried watercress consumption on the gut microbiome using metagenomics sequencing.This study will provide information regarding biomarkers of response to freeze-dried watercress in a pancreatic cancer model. The long-term goal is to develop a strategy to prevent the progression of PanIN lesions to pancreatic cancer using a whole-food approach.
Animal Health Component
50%
Research Effort Categories
Basic
50%
Applied
50%
Developmental
(N/A)
Goals / Objectives
The overarching goal of the project is to characterize the efficacy of watercress (Nasturtium officinale) on preventing the development and progression of early lesions of pancreatic intraepithelial neoplasia to more advanced lesions and pancreatic cancer, and on modulating the gut microbiome.The objectives of this project are (1) to determine the efficacy of freeze-dried watercress to prevent the development of precursor pancreatic intraepithelial neoplasia lesions to invasive pancreatic adenocarcinoma, by using a transgenic animal model which resembles histopathological features of the human disease, and (2) to characterize the effect of freeze-dried watercress consumption on the gut microbiome by shotgun metagenomics sequencing.
Project Methods
Specific Aim 1. Determine the efficacy of oral administration of freeze-dried watercress to prevent the development and progression of pancreatic intraepithelial neoplasia (PanIN) lesions to pancreatic cancer using the LSL-KrasG12D/+;Pdx1Cre/+ transgenic mouse model.The methods used in specific aim 1 will involve the transgenic animal model LSL-KrasG12D/+;Pdx1Cre/+ which resembles histopathological features of human pancreatic cancer. In this model mice develop pancreatic cancer within a physiologic microenvironment and present progressive stages of pancreatic cancer starting from early precursor intraepithelial hyperplasia lesions PanIN-1 to intermediate lesions PanIN-2, and then to advanced PanIN-3 lesions which can progress to pancreatic adenocarcinoma in older mice. The progressive development to high-grade PanIN lesions makes this model suitable for prevention and interception studies because it provides a long period of intervention during the early, preinvasive states. This specific aim will evaluate whether oral administration of freeze-dried watercress prevents the onset and/or progression of PanIN lesions to invasive pancreatic adenocarcinoma.The preventive effect of the watercress intervention compared with vehicle (control) will be assessed based on the following primary and secondary endpoints. Primary endpoints: (1) incidence and histopathological grading of PanIN lesions; and (2) incidence of pancreatic cancer; and Secondary endpoints: (3) Analysis of proliferation, apoptosis, and cell cycle markers in pancreatic tissue. Pancreas weights and incidence of metastasis will be also recorded and compared between watercress-treated group and control group.Specific Aim 2. Determine the impact of oral administration of freeze-dried watercress on the gut microbiome using shotgun metagenomic sequencing analysis.The methods used in specific aim 2 will involve shotgun metagenomic sequencing analysis of the gut microbiome. The shotgun metagenomic sequencing is used to determine the effect of watercress administration on the gut microbiome taxonomic composition, and to characterize the relative abundance of taxa as compared to vehicle-treated control.Overall, this study will provide information necessary in developing biomarkers of response to freeze-dried watercress and it will characterize the impact of freeze-dried watercress on the gut microbiome.