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Contributions of the Adipose Tissue to the Development of Pancreatic Cancer

Award Number: R01CA279707
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/08/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Contributions of the Adipose Tissue to the Development of Pancreatic Cancer - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $523,133 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	001	2	6/13/2025	NON-COMPETING CONTINUATION	$52,312
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	2	1/7/2025	NON-COMPETING CONTINUATION	$470,821
														Subtotal = $523,133

Issue Date FY: 2024 ( Subtotal = $506,842 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	1	2/8/2024	NEW	$506,842
														Subtotal = $506,842

Grand Total All Awards = $1,029,975

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Contributions of the Adipose Tissue to the Development of Pancreatic Cancer

Award Number: R01CA279707

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/08/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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