Stromal Contribution to Pancreatic Cancer Pathogenesis.

Abstract

The overarching goal of this work is to understand the contribution of the stroma to pancreatic tumorigenesis. Pancreatic cancer is among the deadliest of human malignancies and few specific treatments exist for this disease. A hallmark of pancreatic cancer is an extensive desmoplastic stroma consisting of fibroblasts, immune cells, and extracellular matrix. The signaling pathways and cellular components involved in inducing this desmoplastic reaction are an area of active investigation, with the hope of elucidating pathways to target in the clinic. Overexpression of the Hedgehog (HH) ligand occurs in roughly 75% of human pancreatic cancers. Interestingly, HH ligands secreted by the tumor cells act on the tumor stroma to activate signaling in a paracrine manner. However, pathway components that activate hedgehog signaling in the target cells are not fully elucidated, and represent potential druggable targets.

In the first part of this dissertation, I determined the function of three HH coreceptors, Boc, Cdon, and Gas1, on pancreatic tumor growth. While inhibition of HH signaling proved effective in early preclinical tests, clinical trials in humans were terminated due to acceleration of disease. My work indicated that the dosage of HH signaling is an important consideration in pancreatic cancer; while a complete blockade of the pathway abrogated tumor growth, partial inhibition, such as that achieved clinically, led to larger tumors, possibly accounting for the disappointing clinical trials.

Next, I studied the role of the HH pathway on pancreatitis and recovery. Pancreatitis is a risk factor for pancreatic cancer, and currently no pancreatitis-specific treatments exist. Here, I identify a role for Gli1, a HH transcription factor, in pancreatitis and repair. Lastly, I characterized the role of the mesenchymal stem cell (MSC) in pancreatic cancer. Fibroblasts in the tumor microenvironment are treated as a homogenous group of cells, despite evidence that multiple subtypes exist. One such subtype is the multipotent MSC, which has profound effects on tumorigenesis in several solid tumors. In pancreatic cancer, I found that MSCs promote tumor growth by polarizing macrophages to a tumor-promoting subtype.

Taken together, this dissertation work will provide insight into the complex and dynamic microenvironment of pancreatic cancer.