Targeting Uridine Metabolism in Pancreatic Cancer

Abstract public domain (NIH RePORTER)

ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is projected to become the second leading cause of cancer death in the United States by 2030, despite its relatively low incidence. This poor prognosis reflects profound therapeutic resistance and an incomplete understanding of pancreatic tumor biology. PDA tumors are distinguished by a heterogeneous tumor microenvironment, hypovascularity, and deregulated metabolism. PDA cells adapt to limited nutrient availability by acting as highly flexible nutrient scavengers and recyclers, switching from canonical nutrient sources to alternative inputs when individual metabolic pathways are targeted. To define the nutrients and pathways PDA cells use under nutrient limitation, we designed an arrayed nutrient screen and found that PDA cells use uridine, a non-DNA nucleoside, as a fuel source when glucose is restricted. Uridine catabolism requires uridine phosphorylase 1 (UPP1), which liberates ribose to fuel bioenergetic pathways. We further found that PDA tumors express elevated UPP1, high UPP1 predicts worse overall patient survival, UPP1 expression increases during energy stress, and UPP1 deletion blunts tumor growth in immunocompetent mouse models. These observations reveal an important role for alternative fuel sources and metabolic crosstalk in pancreatic tumor metabolism and identify critical knowledge gaps. The overall objective of this proposal is to define how uridine metabolism supports PDA tumor growth. We hypothesize that PDA cells use uridine to survive nutrient stress and that uridine metabolism promotes an immunosuppressive tumor microenvironment, such that disrupting this pathway will facilitate T cell infiltration and tumor control. In Aim 1, we will use molecular biochemistry and mass spectrometry to define the source(s) of uridine available to pancreatic cancer cells and determine the biochemical and signaling pathways that regulate UPP1 expression and uridine metabolism. In Aim 2, we will determine how uridine metabolism supports tumor growth by testing whether it promotes tumor growth through cell-autonomous effects and by altering other cell types in the tumor microenvironment. Vertebrate mouse models are required because the proposed studies examine tumor metabolism, immune cell interactions, and therapeutic responses within an intact tumor microenvironment that cannot be fully recapitulated using cell culture, organoid, or computational models. Immunocompetent syngeneic and genetically engineered PDA mouse models are essential to assess the role of UPP1-dependent uridine metabolism in endogenous tumor growth and anti-tumor immunity. Completion of this proposal will define the role of alternative fuel sources and metabolic crosstalk pathways in PDA and may identify new therapeutic opportunities.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Cancer cells rewire their metabolic programs to support tumor growth. We found that pancreatic cancer cells can metabolize the nucleoside uridine when glucose is scarce, and the inhibition of this process blunts tumor growth. This research proposal will define the mechanisms by which uridine metabolism is regulated to reveal new drug targets and therapies for pancreatic cancer.