Fig. 2: Uridine-derived ribose supports nutrient-restricted PDA.

a, RMA of four PDA cell lines supplemented with glucose, uridine or ribose under nutrient-limiting culture conditions (0 mM glucose, 0.3 mM glutamine and 5% dialysed FBS). b,c, Intracellular and extracellular uridine and uracil after 24 h culture of PATU8988S cells in medium with no glucose and 10% dialysed FBS with or without 1 mM uridine as measured by LC–MS. d–f, Mass isotopologue distribution of carbon derived from [¹³C₅]uridine in uridine, UMP and UTP (d), ATP and NAD⁺ (e) and phosphoenolpyruvate (PEP), lactate and citrate (f) in the indicated cell lines after 24 h culture with 1 mM uridine. g, Isotope tracing showing [¹³C₅]uridine-derived carbon labelling in subcutaneous (sub-Q) or orthotopically (ortho) implanted KPC 7940b tumours collected 1 h after injecting the mice with 0.2 M [¹³C₅]uridine. F6P, fructose-6-phosphate; R5P, ribose-5-phosphate; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; h, Absolute quantification via metabolomics of uridine and uracil concentration in the TIF of orthotopic PDA tumours from syngeneic mouse KPC cells. i, Absolute quantification via metabolomics of glucose concentration in the pancreatic TIF and plasma of mice orthotopically implanted with KPC 7490b syngeneic tumours. j,k, Mass isotopologue distribution of [¹³C₅]uridine ribose-derived carbon after 24 h culture of ASPC1 and PATU8988S cells in medium supplemented with 1 mM or 0.1 mM uridine and each with 5 mM or 0.1 mM glucose. j, Uridine. k, PRPP, UDP-GlcNAc, NAD⁺, 3-phosphoglycerate/2-phosphoglycerate (3PG/2PG), lactate and citrate. PRPP, phosphoribosyl pyrophosphate. l. Schematic depicting the fate of uridine-derived ribose carbon in PDA cells actively catabolizing uridine. Glyceraldehyde-3-P, glyceraldehyde-3-phosphate; HBP, hexosamine biosynthetic pathway; PPP, pentose phosphate pathway; ribose-1-P, ribose-1-phosphate; SBP, serine biosynthesis pathway. See Methods ‘Statistics and reproducibility’ section for additional information.