Defining the role of uridine metabolism in pancreatic tumorigenesis

Active Project Grant Awarded Last action

Award ID
F31CA310311
Recipient
Awarding agency
Obligated
$88,316

Award facts

Assistance listing
93.398 Cancer Research Manpower
Completion date 0% complete
Originally
Place of performance
Ann Arbor, MI 48109, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy often diagnosed at late stages of the disease when treatment options offer little hope. Thus, IT is crucial to better characterize pancreatic tumorigenesis for the identification of novel markers for early diagnosis and strategies to block malignant progression. During the initiation of PDA, acinar cells in the normal pancreas undergo acinar-to-ductal metaplasia (ADM), progressing to pancreatic intraepithelial neoplasias (PANINS) and then to PDA. In established disease, previous research from our group demonstrated that the cancer cells use uridine as an alternative metabolic substrate under glucose restriction through the activity of uridine phosphorylase 1 (UPP1). UPP1 is upregulated in PDA, and knockout of UPP1 reduces tumor growth. Similarly, I recently discovered that UPP1 is upregulated during ADM and in response to nutrient stress. These observations suggest that uridine metabolism through UPP1 may support the earliest stages of disease initiation and may provide a new therapeutic inroad to block or track early disease. The long-term goal of this work is to characterize the metabolic requirements for pancreatic tumorigenesis. The overall objective of this proposal is to 1) identify how UPP1 is regulated during nutrient stress and 2) determine the role of UPP1 and uridine metabolism during pancreatic tumorigenesis. This work will test the hypothesis that UPP1 supports ADM and oncogenic progression by freeing uridine-derived ribose as a metabolic fuel for energy-stressed cells. These goals will be achieved through the following specific aims. In aim 1, this work will identify the mechanisms of UPP1 regulation during nutrient stress. Preliminary data shows that UPP1 expression in PDA cells increases in response to glucose and uridine depletion, suggesting that UPP1 is induced to adapt cellular metabolism, which I propose is critical during metaplasia. To address this objective, canonical nutrient sensors will be tested for their impact on UPP1 expression and function during nutrient starvation. In aim 2, this project will identify the requirement for UPP1 during pancreatic tumorigenesis. Preliminary data shows UPP1 expression is elevated during pancreatic inflammation and ADM, implicating a role for UPP1 during pancreatic tumorigenesis. I will use EX vivo ADM assays of primary human and mouse acinar cells, as well as a novel UPP1 floxed mouse in vivo with pharmacologic and genetic methods to determine the role of uridine metabolism in metaplasia and pancreatic tumorigenesis. Together, these aims will uncover how uridine metabolism and UPP1 regulation support pancreatic tumorigenesis. This research will provide critical new insights into the drivers of pancreatic transformation and oncogenesis, which may inform new dietary or therapeutics mechanisms to diagnose and block pancreatic cancer at its earliest stages.

Transactions

Action Obligated Date
Amendment $44,158
Amendment $0
Original award $44,158

Quick answers

Who received award F31CA310311?

F31CA310311 was awarded to Regents Of The University Of Michigan by National Cancer Institute (National Institutes of Health) on December 1, 2026.

How much is award F31CA310311 worth?

$88,316 has been obligated on F31CA310311.

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