Cholesterol efflux pathways hinder KRAS-driven lung tumor progenitor cell expansion

被引：14

作者：

Guilbaud, Emma ^{[1
,2
]}

Barouillet, Thibaul ^{[1
]}

Ilie, Marius ^{[3
]}

Borowczyk, Coraline ^{[1
]}

Ivanov, Stoyan ^{[1
]}

Sarrazy, Vincent ^{[1
]}

Vaillant, Nathalie ^{[1
]}

Ayrault, Marion ^{[1
]}

Castiglione, Alexia ^{[1
]}

Rignol, Guylene ^{[1
]}

Brest, Patrick ^{[3
]}

Bazioti, Venetia ^{[4
]}

Zaitsev, Konstantin ^{[5
]}

Lebrigand, Kevin ^{[6
]}

Dussaud, Sebastien ^{[7
]}

Magnone, Virginie ^{[6
]}

Bertolotto, Corine ^{[1
]}

Marchetti, Sandrine ^{[1
]}

Irondelle, Marie ^{[1
]}

Goldberg, Ira ^{[8
]}

Huby, Thierry ^{[7
]}

Westerterp, Marit ^{[4
]}

Gautier, Emmanuel L. ^{[7
]}

Mari, Bernard ^{[6
]}

Barbry, Pascal ^{[6
]}

Hofman, Paul ^{[3
]}

Yvan-Charvet, Laurent ^{[1
]}

机构：

[1] Univ Cote Azur, Ctr Mediterrane Med Mol C3M, INSERM, Atip Avenir,U1065,Federat Hosp Univ FHU OncoAge, F-06204 Nice, France

[2] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY 10065 USA

[3] Univ Cote Azur, Univ Hosp Federat OncoAge, Hosp Integrated Biobank BB,CNRS, UMR7284,Inst Res Canc & Aging Nice IRCAN,INSE, 06107, F-00025 Nice, France

[4] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands

[5] ITMO Univ, Comp Technol Dept, St Petersburg, Russia

[6] Univ Cote Azur, Inst Pharmacol Mol & Cellulaire IPMC, CNRS, UMR7275,FHU OncoAge, Nice Sophia Antipolis, France

[7] Sorbonne Univ, INSERM, UMR S 1166, ICAN, UMR S 1166 ICAN, F-75013 Paris, France

[8] NYU Langone Med Ctr, Div Endocrinol, Diabet & Metab, New York, NY USA

来源：

CELL STEM CELL | 2023年 / 30卷 / 06期

基金：

欧洲研究理事会;

关键词：

STEM-CELLS; CANCER; INFLAMMATION; PROGRESSION; GROWTH; ABCG1; MICROENVIRONMENT; TRANSPORTERS; MACROPHAGES; SURVIVAL;

D O I：

10.1016/j.stem.2023.05.005

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Cholesterol efflux pathways could be exploited in tumor biology to unravel cancer vulnerabilities. A mouse model of lung-tumor-bearing KRASG12D mutation with specific disruption of cholesterol efflux pathways in epithelial progenitor cells promoted tumor growth. Defective cholesterol efflux in epithelial progenitor cells governed their transcriptional landscape to support their expansion and create a pro-tolerogenic tumor microenvironment (TME). Overexpression of the apolipoprotein A-I, to raise HDL levels, protected these mice from tumor development and dire pathologic consequences. Mechanistically, HDL blunted a positive feedback loop between growth factor signaling pathways and cholesterol efflux pathways that cancer cells hijack to expand. Cholesterol removal therapy with cyclodextrin reduced tumor burden in progressing tumor by suppressing the proliferation and expansion of epithelial progenitor cells of tumor origin. Local and sys-temic perturbations of cholesterol efflux pathways were confirmed in human lung adenocarcinoma (LUAD). Our results position cholesterol removal therapy as a putative metabolic target in lung cancer progeni-tor cells.

引用

页码：800 / +

页数：28

共 58 条

[51] The Metabolic Profile of Tumors Depends on Both the Responsible Genetic Lesion and Tissue Type [J].