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

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.

Automated summary

Cholesterol efflux pathways play a role in tumor biology and can be targeted as a metabolic therapy for lung cancer. Disruption of these pathways in epithelial progenitor cells promotes tumor growth and creates a pro-tolerogenic tumor microenvironment. Increasing HDL levels protects against tumor development by inhibiting the positive feedback loop between growth factor signaling and cholesterol efflux pathways. Cholesterol removal therapy using cyclodextrin reduces tumor burden by suppressing the proliferation and expansion of tumor progenitor cells.