SUMMARY
Intraductal papillary mucinous neoplasm (IPMN) is one of the two most common precursor lesions leading to
the development of pancreatic ductal adenocarcinoma (PDA). IPMNs comprise a heterogeneous group of
tumors with a wide range of grades and histotypes, and the emergence of single-cell RNA sequencing (RNA-
seq) and multiplex digital spatial profiling have characterized unique cell populations, including dysplastic
epithelial and immune cells, within the heterogeneous tumor microenvironment that carry signature gene
expressions, which could be used as markers for disease progression. However, further studies are needed to
delineate the biological interaction between epithelial subtypes and immune cells that drive IPMN lesion
development. Genetically engineered mouse models (GEMMs) for IPMN have been established using
oncogenic mutations and disruption of tumor suppressors found in human IPMN samples. Analyses of these
IPMN GEMMs have provided important mechanistic insight into the underlying progression of these
precancerous lesions to invasive PDA. Our group has developed a novel KNGC model (KRasG12D, nuclear
GSK-3ß, PDX1-Cre) resulting in the development of IPMN through the retention of a ductal progenitor pool
defined by being AGR2+/AQP5+/DBA-, which are also detected in the IPMN KGC (KRasG12D, GNASR201C, Cre)
model and patient samples with IPMN. Additionally, KNGC animals show progressive desmoplasia beginning
as early as 4 weeks of age with increased immune cell infiltration, which we hypothesize is due to the high
expression of CX3CL1 (fractalkine), a chemokine involved in the recruitment of CX3CR1-expressing
monocytes, which are known to promote fibrosis in various disease models upon differentiation into type 2
macrophages. Indeed, our preliminary data from CX3CR1 heterozygous (CX3CR1GFP/+) and homozygous
(CX3CR1GFP/GFP) knockout in the KNGC model shows an enrichment of GFP signal in M2-like macrophages in
the IPMN lesions of the KNGCXGFP/+ model, whereas KNGCXGFP/GFP animals had a paucity of M2-like
macrophages, substantially reduced desmoplasia and impaired development of IPMN. It is our central
hypothesis that the ductal expression of CX3CL1 results in the accumulation of M2-like macrophages,
which facilitate the development and progression of IPMN in KNGC mice. We will address our hypothesis
through the following specific aims: (1) Determine the role of CX3CL1 in promoting IPMN development and
desmoplasia in KNGC mice, and (2) Determine the role of CX3CR1 in promoting immune suppressive
environment in KNGC mice. Altogether, this project will provide a mechanistic understanding of the CX3CL1-
CX3CR1 axis in the generation of an immune/stroma microenvironment facilitating IPMN development. The
information obtained in pursuit of the aims might lead to the identification of novel biomarkers that could be
used to monitor or treat patients with IPMN.