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

Emma Guilbaud*, Thibault Barouillet, Marius Ilie, Coraline Borowczyk, Stoyan Ivanov, Vincent Sarrazy, Nathalie Vaillant, Marion Ayrault, Alexia Castiglione, Guylène Rignol, Patrick Brest, Venetia Bazioti, Konstantin Zaitsev, Kevin Lebrigand, Sébastien Dussaud, Virginie Magnone, Corine Bertolotto, Sandrine Marchetti, Marie Irondelle, Ira GoldbergThierry Huby, Marit Westerterp, Emmanuel L. Gautier, Bernard Mari, Pascal Barbry, Paul Hofman, Laurent Yvan-Charvet*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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 systemic 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 progenitor cells.

Original languageEnglish
Pages (from-to)800-817.e9
JournalCell stem cell
Volume30
Issue number6
DOIs
Publication statusPublished - 1-Jun-2023

Keywords

  • cholesterol efflux
  • high-density lipoprotein
  • KRAS
  • lung adenocarcinoma
  • tumor microenvironment

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