Spatially resolved profiling of colorectal cancer lipid biochemistry via DESI imaging mass spectrometry to reveal morphology-dependent alterations in fatty acid metabolism

Title: Spatially resolved profiling of colorectal cancer lipid biochemistry via DESI imaging mass spectrometry to reveal morphology-dependent alterations in fatty acid metabolism
Authors: Mirnezami, R
Veselkov, K
Strittmatter, N
Goldin, RD
Kinross, JM
Stebbing, J
Holmes, E
Darzi, AW
Nicholson, JK
Takats, Z
Item Type: Conference Paper
Abstract: Background: Lipid metabolic alterations are recognised as potential oncogenic triggers that promote malignant transformation. Here we performed spatially-resolved profiling of lipid signatures in colorectal cancer (CRC) tissue and matched healthy mucosa using desorption electrospray ionisation imaging mass spectrometry (DESI-MSI). The objectives of this study were to comprehensively define the CRC ‘lipidome’ and to assess lipid signatures in discrete histological regions-of-interest, specifically morphologically bland peri-tumoural epithelium (PT-e) and tumour stroma (T-s). Methods: Fresh frozen tissue sections from 42 patients with confirmed CRC were subjected to negative-ion mode DESI-MSI analysis. Mass spectra in the 200-1000 m/zrange were collated from CRC epithelium (CRC-e), PT-e, T-s and healthy tumour-remote epithelium (TR-e). Spectral signatures were subjected to multivariate analysis using a recursive maximum margin criterion (RMMC) algorithm operating in MATLAB. Results: Increased levels of long/very-long chain fatty acids (LCFA/VLCFA) were seen in CRC-e compared with TR-e(AUC = 0.99). Correspondingly, increased expression of lipogenic and elongase enzymes was found on IHC. Transmission electron microscopy was performed to evaluate peroxisomal distribution and morphology in CRC-e, as these organelles metabolise LCFA/VLCFA through β-oxidation, to negligibly low levels, in healthy cells. No discernible difference in peroxisomal distribution, abundance or structure was found between CRC-e and TR-e. PT-e demonstrated a lipid expression pattern almost identical to that of CRC-e, and markedly different from TR-e (AUC = 0.89). Conclusions: A shift towards increased LCFA/VLCFA production may be an important metabolic trait in CRC facilitated through upregulation of de novo lipogenesis and fatty acid elongation and concurrent impairment of peroxisomal β-oxidation. This phenotype was also observed in morphologically bland PT-e, suggesting that enhanced de novo LCFA/VLCFA biosynthesis and impaired peroxisomal function may represent important steps in peri-tumoural field cancerisation.
Issue Date: 20-May-2016
Date of Acceptance: 1-May-2016
URI: http://hdl.handle.net/10044/1/64022
DOI: https://dx.doi.org/10.1200/JCO.2016.34.15_suppl.e15104
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology
Journal / Book Title: Journal of Clinical Oncology
Volume: 34
Issue: 15_suppl
Copyright Statement: © 2016 American Society of Clinical Oncology
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
Funder's Grant Number: RD207
NIHR-RP-011-053
Conference Name: Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO)
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Start Date: 2016-06-03
Finish Date: 2016-06-07
Conference Place: Chicago, IL
Online Publication Date: 2016-05-20
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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