Data from Integrated Metabolomics and Spatial Transcriptomics of Cystic Pancreatic Cancer Precursors Reveals Dysregulated Polyamine Metabolism as a Biomarker of Progression
Year: 2025
Type: other
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.
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
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4411285716