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. 2025 Jun 13;31(12):2454-2465.
doi: 10.1158/1078-0432.CCR-24-2931.

Integrated Metabolomics and Spatial Transcriptomics of Cystic Pancreatic Cancer Precursors Reveals Dysregulated Polyamine Metabolism as a Biomarker of Progression

Ricardo A León-Letelier  1 , Yihui Chen  1 , Rongzhang Dou  1 , Ehsan Irajizad  2 , Michele T Yip-Schneider  3 , Ranran Wu  1 , Rahmah Ejaz  1 , Hamid K Rudsari  2 , Yaxi Li  1 , Rachelle Spencer  1 , Riccardo Ballarò  1 , Jody Vykoukal  1 , Mark Hurd  4 , Jennifer B Dennison  1 , Kim-Anh Do  2 , Anirban Maitra  4 , Jianjun Zhang  5 , Samir Hanash  1 , C Max Schmidt  3 , Johannes F Fahrmann  1
Affiliations

Integrated Metabolomics and Spatial Transcriptomics of Cystic Pancreatic Cancer Precursors Reveals Dysregulated Polyamine Metabolism as a Biomarker of Progression

Ricardo A León-Letelier et al. Clin Cancer Res. .

Abstract

Purpose: We conducted metabolomics and spatial cell transcriptomics of intraductal papillary mucinous neoplasms (IPMN), recognized pancreatic cancer precursors, to identify oncometabolites that inform upon risk of malignancy of IPMNs.

Experimental design: Untargeted metabolomic analyses were performed on cystic fluid from 125 patients with low-grade (LG) dysplasia or high-grade (HG) dysplasia with/without concurrent pancreatic ductal adenocarcinoma (PDAC; IPMN/PDAC). Predictive performance of individual metabolites for identifying HG or PDAC/IPMN was determined and compared with CA19-9 performance. Data were intersected with metabolic profiles of resected IPMN tissues and murine Kras;Gnas IPMN cell lines as well as spatial and single-cell transcriptomics of IPMNs.

Results: A total of 388 metabolites were quantified in cystic fluid, of which 69 were differential (P-value < 0.05) between cases (HG IPMN + IPMN/PDAC) and patients with LG IPMN. Spermidine and spermine biosynthesis and catabolism was identified as the top perturbed metabolic pathway (FDR-adjusted P-value < 0.0001). Increases in cystic fluid spermidine, n-acetylputrescine, acetylspermidine, diacetylspermidine, diacetylspermine, and acetylcadaverine were associated elevated risk of harboring HG or IPMN/PDAC. An OR rule comprising CA19-9, n-acetylputrescine, acetylspermidine, and diacetylspermine achieved 54.8% sensitivity for detecting HG IPMN and IPMN\PDAC. CA19-9 alone yielded sensitivity of 11.9% (McNemar Test P-value < 0.001). Polyamines were elevated in IPMN\PDAC tissues compared with LG IPMN tissues; spatial and single-cell transcriptomic data revealed transcript levels of polyamine-metabolizing enzymes to be elevated in neoplastic epithelium and tumor-associated macrophages.

Conclusions: Cystic fluid polyamines offer utility for determining risk of malignancy of IPMNs that is complementary to CA19-9 and that has potential to aid in clinical management of patients with IPMNs.

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Conflict of interest statement

Conflict of interest statement: A.M. is a consultant for Tezcat Biosciences and is named on a patent that has been licensed to Thrive Earlier Detection (an Exact Sciences company). The remaining authors declare no potential conflicts of interest.

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