Cholesterol efflux pathways could be exploited in tumor biology to unravel cancer vulnerabilities. A mouse model of lung-tumor-bearing KRAS^G12D 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.

可以在肿瘤生物学中利用胆固醇流出途径来揭示癌症的脆弱性。携带肺肿瘤的 KRAS ^{G12D小鼠模型}特定破坏上皮祖细胞中胆固醇流出途径的突变促进了肿瘤生长。上皮祖细胞中有缺陷的胆固醇流出控制着它们的转录景观，以支持它们的扩张并创造一个促耐受性肿瘤微环境 (TME)。载脂蛋白 AI 的过度表达可提高 HDL 水平，从而保护这些小鼠免受肿瘤发展和可怕的病理后果的影响。从机制上讲，HDL 削弱了生长因子信号通路和癌细胞劫持以扩张的胆固醇流出通路之间的正反馈回路。使用环糊精的胆固醇去除疗法通过抑制肿瘤起源的上皮祖细胞的增殖和扩张来减少进展性肿瘤中的肿瘤负荷。在人肺腺癌 (LUAD) 中证实了胆固醇流出途径的局部和全身扰动。我们的结果将胆固醇清除疗法定位为肺癌祖细胞的假定代谢靶点。