Project Summary
Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a cancer that has a dismal 5-year
survival rate due to limitations in prevention and treatment. Obesity promotes PDAC tumorigenesis and
worsens survival by increasing systemic inflammation, metabolic dysfunction, and chemotherapy resistance,
but the mechanisms that drive tumorigenesis in obesity are unknown. Deleting lipocalin 2 (LCN2) in obese
genetically engineered mouse models (GEMMs) of PDAC decreases inflammation in the tumor
microenvironment and increases survival. LCN2 can bind lipid ligands like fatty acids (FAs), which are
dysregulated in the plasma and adipose tissue of obese PDAC subjects. Linoleic acid can suppress pro-
inflammatory signals through several pathways, including inhibiting LCN2’s binding to matrix
metalloproteinase-9. We observe that linoleic acid was lower in the plasma and arachidonic acid levels to be
highly abundant in the adipose tissue of obese PDAC patients. Arachidonic acid can be derived from linoleic
acid and then converted into pro-inflammatory prostaglandins by the enzyme cyclooxygenase 2 (COX2). We
have previously shown that inhibiting COX2 in obese PDAC GEMMS reduces PDAC. Through other metabolic
pathways, linoleic acid can be metabolized into anti-inflammatory prostaglandins. Therefore, understanding
how LCN2, linoleic acid, and COX2 function in inflammation and metabolism in obesity may help improve
prevention and treatment of PDAC. Our long-term goal is to determine how excess adiposity and inflammation
due to obesity contributes to PDAC to identify targets for novel prevention and treatment strategies.
HYPOTHESES: 1) Signaling from adipose and immune cells in obesity drives tumor development through
changes in inflammation and FA metabolism in the adipose and tumor microenvironments. 2) Targeting FA
metabolism will slow the development of obesity-associated PDAC and decrease adipose tissue inflammation.
To test our hypothesis, we propose the following aims. AIM 1: Determine the adipose tissue and immune
cell contributions of LCN2 signaling on obesity-associated PDAC. We hypothesize that increasing LCN2
signaling from excess adipose tissue and/or immune cells contributes to obesity-associated PDAC
development, progression, and growth by modulating FA metabolism and inflammation in the tumor and
adipose microenvironments. AIM 2: Determine whether targeting fatty acid metabolism inhibits obesity-
associated PDAC. We hypothesize that increasing dietary linoleic acid levels and inhibiting COX2 will
suppress tumors by modifying KRas activity and prostaglandin biosynthesis to promote anti-inflammatory
signaling in PDAC. IMPACT: We will elucidate the signaling mechanisms that underlie how changes in the
adipose tissue of obese individuals can drive the development and progression of obesity-associated PDAC.
Understanding how adipose-derived factors contribute to obesity-associated tumorigenesis will lead to novel
targets for improving PDAC prevention and treatment and provide a model for future work in other obesity-
associated cancers.