Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer
Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mou...
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doaj-94731872d8ec41e79cf6a6bed5eb809f2021-04-29T04:39:19ZengElsevierJournal of Lipid Research0022-22752020-11-01611113901399Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancerZoe Hall0Catherine H. Wilson1Deborah L. Burkhart2Tom Ashmore3Gerard I. Evan4Julian L. Griffin5Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom; For correspondence: Zoe Hall; For correspondence: Zoe HallDepartment of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Department of Pharmacology, University of Cambridge, Cambridge, United KingdomDepartment of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USADepartment of Biochemistry, University of Cambridge, Cambridge, United KingdomDepartment of Biochemistry, University of Cambridge, Cambridge, United KingdomDepartment of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United KingdomNonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.http://www.sciencedirect.com/science/article/pii/S0022227520437277cholesteryl esterliquid extraction surface analysismass spectrometrylipid metabolismadenocarcinoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zoe Hall Catherine H. Wilson Deborah L. Burkhart Tom Ashmore Gerard I. Evan Julian L. Griffin |
spellingShingle |
Zoe Hall Catherine H. Wilson Deborah L. Burkhart Tom Ashmore Gerard I. Evan Julian L. Griffin Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer Journal of Lipid Research cholesteryl ester liquid extraction surface analysis mass spectrometry lipid metabolism adenocarcinoma |
author_facet |
Zoe Hall Catherine H. Wilson Deborah L. Burkhart Tom Ashmore Gerard I. Evan Julian L. Griffin |
author_sort |
Zoe Hall |
title |
Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer |
title_short |
Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer |
title_full |
Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer |
title_fullStr |
Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer |
title_full_unstemmed |
Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer |
title_sort |
myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2020-11-01 |
description |
Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC. |
topic |
cholesteryl ester liquid extraction surface analysis mass spectrometry lipid metabolism adenocarcinoma |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520437277 |
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