Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Sandra W. Ryeom

Abstract

Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide. The majority of patients with gastric cancer are diagnosed with disseminated disease and even patients diagnosed with early stage disease have high rates

of recurrence. The utility of current mouse models of gastric cancer is limited by slow development of gastric tumors and lack of metastasis. Here I describe a new mouse model of gastric cancer driven by p53 loss, Cdh1 loss, and oncogenic Kras expression in

gastric parietal cells (referred to as ACKPY mice). I generated these mice to investigate the contribution of oncogenic Kras to the progression of gastric cancer given the high rate of mutation and amplification of the RTK/Ras pathway identified in gastric cancer

patients. These mice develop mixed-type gastric adenocarcinomas with metastases to lymph nodes, lung, and liver. Oncogenic Kras and loss of Trp53 is sufficient to drive rapid carcinogenesis in a variety of models. Therefore, I tested if loss of E-cadherin was

necessary for the onset of gastric adenocarcinoma in gastric parietal cells by generating ACKPY mice with one or two alleles of wild-type Cdh1 (E-cadherin). E-cadherin expression significantly increased survival and the limited number of mice with gastric

tumors have tumors that were focal in nature, suggesting an additional event was necessary for gastric tumorigenesis. Loss of E-cadherin expression was observed in some of these tumors, suggesting that its loss may be necessary for gastric tumorigenesis in this model. I show that loss of E-cadherin in our model increases β-catenin signaling and that inhibition of β-catenin signaling prolonged survival of ACKPY mice. Microarray data comparing gene expression in stomachs harvested from Cdh1fl/fl and Cdh1fl/+ mice showed a correlation between E-cadherin loss and upregulation of oncogenic Kras signaling. Gene sets regulated by each of the main Kras effector pathways were overrepresented in our microarray data. Examination of ERK phosphorylation revealed that

E-cadherin likely does not regulate MAPK activity in our model. The upregulation of oncogenic Kras target genes that result from the loss of E-cadherin may alternatively be explained by E-cadherin regulation of other Kras effector pathways.

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