TABLE OF CONTENTS

LIST OF ABBREVIATIONS………………………………………………………………………………………….1

INTRODUCTION…………………………………………………………………………………………….2
• Background
• Cell of Origin
• Genetic Landscape of Pancreatic Cancer
• Precursor Lesions
• Mutational Processes
• Tumoral Heterogeneity
• Molecular Subtyping of Pancreatic Cancer
• Deranged Signaling Pathways / Molecular Aberrations
• Tumor Microenvironment
• Metabolic Reprogramming
• Immune Response in Pancreatic Cancer is Unclear
• Pre-clinical Modeling of Pancreatic Cancer
STATEMENT OF PURPOSE……………………………………………………………………………………….18
METHODS…………………………………………………………………………………………19
• Acquisition of human specimens
• Isolation and culture of murine pancreatic organoids
• Isolation and culture of human PDAC organoids
• Isolation of primary murine PDAC cell lines
• Genetic manipulation of murine pancreatic organoids
• In vivo mouse assays
• Immunohistochemical analysis of tumors
• Sanger sequencing of organoids
• Development of organoid-T cell co-culture model systems
RESULTS…………………………………………………………………………………………..26
• KP-NINJA mouse model provides substrate for creation of immunogenic murine
organoid models of PDAC
• In vitro transformed murine pancreatic organoids form tumors that are histologically
similar to early lesions found in human PDAC
• Serial in vivo transfer of transformed murine pancreatic organoids results in
progressively more advanced tumors
• Expression of neoantigens in murine PDAC organoids elicits effective immune response
in mouse
• Expression of neoantigens in murine PDAC organoids promotes T cell infiltration in T
cell-organoid co-culture model
• Assembly of human PDAC organoid library
DISCUSSION…………………………………………………………………………………….33
REFERENCES…………………………………………………………………………………36
FIGURES…………………………………………………………………………………..38
TABLES………………………………………………………………………………………..48