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

Authors

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

Language

English

Publication Date

6-13-2025

Journal

Clinical Cancer Research

DOI

10.1158/1078-0432.CCR-24-2931

PMID

40184234

PMCID

PMC12165819

PubMedCentral® Posted Date

12-13-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Metabolomics, Biomarkers, Tumor, Polyamines, Pancreatic Neoplasms, Disease Progression, Female, Male, Carcinoma, Pancreatic Ductal, Middle Aged, Animals, Transcriptome, Aged, Mice, Gene Expression Profiling, Pancreatic Intraductal Neoplasms, Cell Line, Tumor

Published Open-Access

yes

Recommended Citation

León-Letelier, Ricardo A; Chen, Yihui; Dou, Rongzhang; et al., "Integrated Metabolomics and Spatial Transcriptomics of Cystic Pancreatic Cancer Precursors Reveals Dysregulated Polyamine Metabolism as a Biomarker of Progression" (2025). Faculty, Staff and Student Publications. 5593.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5593