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

Authors

León-Letelier RA, Chen Y, Dou R, Irajizad E, Yip-Schneider MT, Wu R, Ejaz R, Rudsari HK, Li Y, Spencer R, Ballarò R, Vykoukal J, Hurd M, Dennison JB, Do KA, Maitra A, Zhang J, Hanash S, Schmidt CM, Fahrmann JF

Affiliations

• Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
• Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
• Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
• Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
• Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana.

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.