Investigating Molecular Mechanisms of Drug Resistance in a 3D Cell Culture Model of Pancreatic Cancer
Year: 2017
Type: dissertation
Abstract: Pancreatic cancer is the fourth leading cause of malignancy-related mortality in the United States. Despite decades of intensive research, patient 5-year survival following diagnosis remains below 10%. The high mortality rate can be attributed to lack of effective therapies, and pancreatic cancer resistance to traditional cancer treatment modalities. The goal of this study was to identify molecular mechanisms of pancreatic cancer resistance to treatment and ideally characterize novel drug targets, which may prove efficacious in combating this devastating disease. To achieve this, we optimized a 3D culture model system that utilized Matrigel as a basement membrane mimetic, facilitating cell-to-cell adhesion as well as cell-to-extracellular-matrix interactions, similar to tumor signaling dynamics in vivo. In this cell culture system, pancreatic cancer cells recapitulated oncogene addiction and other in vivo characteristics of disease. We chose to study the molecular mechanism of MAPK blockade in this 3D culture system and found that pancreatic cancer cells relied on β1 integrin signaling to mediate resistance in the context of MAPK blockade. Furthermore, β1 integrin signaling was found to be necessary for upregulation of MAPK signaling in the absence of extracellular matrix signaling. These findings reveal a novel role for β1 integrin in pancreatic cancer pathogenesis and give insight into the molecular mechanisms that drive disease.
Author: Arthur Brannon
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2981378170