Abstract
It has become well recognized that inflammation from chronic pancreatitis is associated an 8-fold increased risk
for the development of pancreatic cancer. When cells are injured or stressed, they can transform to a cell with a
different phenotype through a process called metaplasia. In the pancreas, acinar-ductal metaplasia (ADM)
occurs with pancreatitis and this process is usually reversible. However, with chronic inflammation or maturation
arrest, the ductal phenotype cells do not reverse to their normal acinar phenotype but may progress to pancreatic
intraepithelial neoplasia (PanINs) and pancreatic cancer. There is a gap in our understanding of the mechanisms
involved in this recovery or loss of the ability to recover. Our lab has been studying G-protein coupled receptors
and found that the cholecystokinin-B receptor (CCK-BR) that is found in ductal cells but not acinar cells becomes
expressed during chronic pancreatitis and PanIN formation, and is markedly over-expressed in pancreatic
cancer. Treatment with a CCK-receptor antagonist, proglumide, hastens recovery of ADM, decreases
inflammation, and restores the pancreas to a normal phenotype. In more advanced disease with PanINs or with
pancreatic cancer, proglumide treatment also alters the pancreas extracellular matrix or tumor
microenvironment, by decreasing collagen production from pancreatic stellate cells or cancer-associated
fibroblasts and changing the immune cell signature to a more normal phenotype. We hypothesize that the
CCK-BR signaling pathway is a novel and key pathway in pancreatic plasticity; strategies to suppress
this pathway will decrease pancreatic cancer. Proglumide has already been tested in human subjects in a
Phase 1 clinical trial and deemed to have a broad safety profile. In this proposal we will study the role of
proglumide and the CCK-BR in pancreatic cell plasticity and how this pathway can be targeted to normalize the
pancreatic phenotype and render it less oncogenic to prevent pancreatic cancer. The following aims are
proposed: Aim #1, Determine how the CCK-BR signaling pathway is involved in acinar-ductal metaplasia; Aim
#2, Examine how activation of the CCK-B receptor pathway modulates pancreatic stellate cells and if CCK-
receptor blockade can change the phenotype to render the fibroblasts less carcinogenic; and Aim #3, Evaluate
how activation of the CCK-BR induces tissue inflammation and polarization of immune cells. In this investigation,
we will use murine models of pancreatitis in wild-type and in CCK-BR-knockout mice with state of the art
techniques as laser microdissection of ADM and stroma, Reverse phase protein array, Mass Cytometry and
RNA sequencing to understand plasticity of pancreatic cells. We will also examine the role of the CCK-BR on
the pancreatic stellate cells in vitro using murine and human cells. Our goal is to understand how proglumide
reprograms a metaplastic or dysplastic pancreas to a more normal phenotype and thus preventing development
of pancreatic cancer.