Student Theses and Dissertations

Date of Award

2018

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Tavazoie Laboratory

Abstract

Pancreatic cancer is a deadly malignancy because it is usually diagnosed at an advanced stage and does not respond to the majority of treatments. More than 80% of patients present with advanced stage disease at the time of diagnosis and metastatic pancreatic cancer has a median survival of eight to eleven months under current standard of care. In the United States, pancreatic cancer is the fourth leading cause of cancer death. Efforts in using targeted agents to treat pancreatic cancer have mostly been fruitless. The dismal survival outcome of this disease and lack of success in clinical trials indicate the necessity for new models and improved approaches toward therapies. Understanding the cellular and physiological basis of metastatic pancreatic cancer is therefore of great interest to the medical and scientific community with regard to developing new targeted therapies and diagnostic biomarkers. The first part of this thesis describes the establishment of two complementary pancreatic cancer metastasis mouse models using in vivo selection of livermetastatic pancreatic cancer cells from their poorly metastatic parental population. The first mouse model utilized a xenograft system, and the second model used a syngeneic system. Transcriptomic profiling was used to identify genes that were differentially expressed between the in vivo selected, highly metastatic cells and their poorly metastatic parental population in both mouse models. This approach identified Neuronal Pentraxin 1 (NPTX1) as a potential metastasis promoter because it was highly expressed in the in vivo selected, highly metastatic cancer cells compared to the poorly metastatic parental cells. Through in vivo functional assays, NPTX1 was found to promote pancreatic cancer progression. NPTX1 was necessary to promote progression of established liver macro-metastases, a rate limiting step in the metastasis cascade. The second part of this thesis presents mechanistic studies that describe NPTX1’s role in promoting cancer cell proliferating under a hypoxic tumor microenvironment. This proliferation advantage allows cancer cells to survive both in the primary tumor and promotes distal organ metastatic colonization. The final part of this study reveals NPTX1 to be clinically relevant in patient samples. NPTX1 was found to be expressed in pancreatic tumor samples, but not in healthy pancreatic tissues. In addition, NPTX1 could be detected in the plasma of the xenograft mouse model, demonstrating the diagnostic and therapeutic potential of this secreted protein in pancreatic cancer.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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