title: Fecal Metabolome in Hmga1 Transgenic Mice with Polyposis: Evidence for Potential Screen for Early Detection of Precursor Lesions in Colorectal Cancer.
abstract: Because colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, more accessible screening tests are urgently needed to identify early stage lesions. We hypothesized that highly sensitive, metabolic profile analysis of stool samples will identify metabolites associated with early stage lesions and could serve as a noninvasive screening test. We therefore applied traveling wave ion mobility mass spectrometry (TWIMMS) coupled with ultraperformance liquid chromatography (UPLC) to investigate metabolic aberrations in stool samples in a transgenic model of premalignant polyposis aberrantly expressing the gene encoding the high mobility group A (Hmga1) chromatin remodeling protein. Here, we report for the first time that the fecal metabolome of Hmga1 mice is distinct from that of control mice and includes metabolites previously identified in human CRC. Significant alterations were observed in fatty acid metabolites and metabolites associated with bile acids (hypoxanthine xanthine, taurine) in Hmga1 mice compared to controls. Surprisingly, a marked increase in the levels of distinctive short, arginine-enriched, tetra-peptide fragments was observed in the transgenic mice. Together these findings suggest that specific metabolites are associated with Hmga1-induced polyposis and abnormal proliferation in intestinal epithelium. Although further studies are needed, these data provide a compelling rationale to develop fecal metabolomic analysis as a noninvasive screening tool to detect early precursor lesions to CRC in humans.
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Williams
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Lingling
authors.initials: L
authors.lastname: Xian
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Tait
authors.initials: T
authors.lastname: Huso
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Jeong-Jin
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: David
authors.initials: D
authors.lastname: Huso
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Cope
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Gang
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: William F
authors.initials: WF
authors.lastname: Siems
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Resar
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Reeves
authors.affiliation: Department of Chemistry, ‡School of Molecular Biosciences, and §Institute of Biological Chemistry, Washington State University , Pullman, Washington 99164, United States.|Department of Medicine, ¶Department of Oncology, and ∥Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Hill
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D055088:Early Detection of Cancer / Q000379:methods*; D005227:Fatty Acids / Q000378:metabolism; D005243:Feces / Q000737:chemistry*; D024003:HMGA Proteins / Q000235:genetics*; D013058:Mass Spectrometry; D055442:Metabolome; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D005227:Fatty Acids; D024003:HMGA Proteins; D010446:Peptide Fragments
keywords: cancer metabolomics; cancer screening; colorectal cancer; high mobility group A1 (HMGA1) chromatin remodeling protein; ion mobility mass spectrometry