Uridine-derived ribose fuels glucose-restricted pancreatic cancer.
Date
2023-06-01ICR Author
Author
Nwosu, ZC
Ward, MH
Sajjakulnukit, P
Poudel, P
Ragulan, C
Kasperek, S
Radyk, M
Sutton, D
Menjivar, RE
Andren, A
Apiz-Saab, JJ
Tolstyka, Z
Brown, K
Lee, H-J
Dzierozynski, LN
He, X
Ps, H
Ugras, J
Nyamundanda, G
Zhang, L
Halbrook, CJ
Carpenter, ES
Shi, J
Shriver, LP
Patti, GJ
Muir, A
Pasca di Magliano, M
Sadanandam, A
Lyssiotis, CA
Type
Journal Article
Metadata
Show full item recordAbstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.
Collections
Subject
Animals
Mice
Carcinoma, Pancreatic Ductal
Pancreatic Neoplasms
Ribose
Tumor Microenvironment
Uridine
Glucose
Cell Division
Cell Line, Tumor
MAP Kinase Signaling System
Uridine Phosphorylase
Humans
Research team
Systems - Precision Med
Language
eng
Date accepted
2023-04-12
License start date
2023-06-01
Citation
Nature, 2023, 618 (7963), pp. 151 - 158
Publisher
NATURE PORTFOLIO