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De novo lipogenesis alters the phospholipidome of esophageal adenocarcinoma

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Title: De novo lipogenesis alters the phospholipidome of esophageal adenocarcinoma
Authors: Abbassi-Ghadi, N
Antonowicz, S
McKenzie, J
Kumar, S
Huang, J
Jones, E
Strittmatter, N
Petts, G
Kudo, H
Court, S
Hoare, J
Veselkov, K
Goldin, R
Takats, Z
Hanna, G
Item Type: Journal Article
Abstract: The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging can support objective diagnosis in minutes using a routine frozen tissue section. However, whether mass spectrometry imaging can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here we used desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariable models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (area-under-curve = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in pre-malignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch ACLY in esophageal adenocarcinoma cells shortened GPL chains, linking de novo lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of pre-malignant tissues and unveils mechanisms of phospholipidomic reprogramming. These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis.
Issue Date: 28-Apr-2020
Date of Acceptance: 23-Apr-2020
URI: http://hdl.handle.net/10044/1/79476
DOI: 10.1158/0008-5472.CAN-19-4035
ISSN: 0008-5472
Publisher: American Association for Cancer Research
Start Page: 2764
End Page: 2774
Journal / Book Title: Cancer Research
Volume: 80
Issue: 13
Copyright Statement: ©2020, American Association for Cancer Research.
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
FATTY-ACID SYNTHASE
HUMAN BRAIN-TUMORS
MASS-SPECTROMETRY
THERAPEUTIC TARGET
LIPID SIGNATURES
LUNG-CANCER
MITOCHONDRIA
CARDIOLIPIN
DIAGNOSIS
MARKER
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2020-04-28
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Medicine