PO.TB10.02 · 肿瘤生物学
肝脏微环境驱动的代谢-表观遗传重编程通过肝祖细胞样可塑性介导转移定植
Hepatic niche driven metabolic-epigenetic reprogramming mediates metastatic colonization through liver progenitor like plasticity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景
肝转移是小细胞肺癌（SCLC）死亡的主要原因，但使转移定植成为可能的器官特异性线索仍知之甚少。我们假设肝脏微环境促进了转移生长所需的干细胞样、高可塑性状态。
方法
我们使用 RNA-seq、ATAC-seq 和代谢组学，结合空间转录组学和原位肝脏定植模型，分析了患者来源的 SCLC 肝转移。通过蛋白定量和 13C-葡萄糖示踪评估区域性缺氧、HIF1alpha 信号和代谢通量。功能研究包括药理学 ACLY 抑制（SB204990）和体内 CRISPR 介导的 ACLY 敲除。
结果
在患者标本和体内模型中，肝脏内的转移性 SCLC 细胞采取了一种独特的干细胞样转录状态，以再生程序的激活和干性基因位点（HNF1A、HNF4A、SOX9、ATF3）的染色质可及性为标志。空间分析揭示邻近肝细胞的肿瘤细胞经历局部缺氧，导致 HIF1alpha 稳定化及 ACLY（一种生成核内乙酰辅酶 A 的关键酶）的转录诱导。ATP-柠檬酸裂解酶（ACLY）依赖性地生成核内乙酰辅酶 A，驱动组蛋白高乙酰化以及在肝谱系转录因子 HNF1A、HNF4A 和 SOX9 处的染色质重塑。肝转移细胞发生糖酵解重编程，这一代谢转变与肝损伤期间的肝细胞再生相平行，提供乙酰辅酶 A 和生物合成前体以支持表观遗传重塑和谱系适应。类似的祖细胞样肝脏可塑性也在其他具有肝趋向性的上皮癌中观察到，包括乳腺癌、结肠癌和非小细胞肺癌，表明一种保守的转移适应模式。ACLY 活性介导了干细胞样状态所需的组蛋白高乙酰化和表观遗传重塑。ACLY 在功能上必不可少。药理学 ACLY 抑制阻断了干细胞样程序的诱导，降低了组蛋白乙酰化以及肝转移细胞的生长速率。CRISPR-ACLY 敲除阻止了重编程表型的获得。在来自乳腺癌、结肠癌和 NSCLC 的肝转移中观察到类似的肝脏微环境诱导的干性特征，提示上皮癌之间存在一种保守机制。
结论
肝脏微环境通过在播散肿瘤细胞中诱导 HIF1alpha-ACLY-乙酰辅酶 A 驱动的干细胞样状态，主动促进转移能力。ACLY 抑制破坏了这种代谢-表观遗传重编程，并显著抑制肝转移生长，凸显 ACLY 作为肝转移可行治疗靶点的价值。
查看英文原文 English abstract
Background
Liver metastasis is a major cause of mortality in small cell lung cancer (SCLC), but the organ-specific cues that enable metastatic colonization are poorly understood. We hypothesized that the hepatic microenvironment promotes a stem-like, high-plasticity state required for metastatic outgrowth.
Methods
We analyzed patient-derived SCLC liver metastases using RNA-seq, ATAC-seq, and metabolomics, combined with spatial transcriptomics and orthotopic liver colonization models. Regional hypoxia, HIF1alpha signaling, and metabolic flux were assessed by protein quantification and 13C-glucose tracing. Functional studies included pharmacological ACLY inhibition (SB204990) and CRISPR-mediated ACLY knockout in vivo.
Results
Across patient specimens and in vivo models, metastatic SCLC cells in the liver adopted a distinct stem-like transcriptional state, marked by activation of regenerative programs and chromatin accessibility at stemness loci (HNF1A, HNF4A, SOX9, ATF3). Spatial profiling revealed that tumor cells adjacent to hepatocytes experienced localized hypoxia, resulting in HIF1alpha stabilization and the transcriptional induction of ACLY, a key enzyme that generates nuclear acetyl-CoA. ATP-citrate lyase (ACLY)-dependent generation of nuclear acetyl-CoA, driving histone hyperacetylation and chromatin remodeling at liver-lineage transcription factors HNF1A, HNF4A, and SOX9. Liver-metastatic cells undergo glycolytic reprogramming, a metabolic shift that parallels hepatocyte regeneration during liver injury, providing acetyl-CoA and biosynthetic precursors to support epigenetic remodeling and lineage adaptation. Similar progenitor-like hepatic plasticity is observed across other epithelial cancers with liver tropism, including breast, colon, and non-small cell lung cancers, indicating a conserved mode of metastatic adaptation. ALY activity mediated histone hyperacetylation and epigenetic remodeling required for the stem-like state. ACLY was functionally essential. Pharmacologic ACLY inhibition blocked the induction of stem-like programs, reduced histone acetylation, and growth rate of liver metastatic cells. CRISPR-ACLY knockout prevented the acquisition of the reprogrammed phenotype. Similar hepatic niche-induced stemness signatures were observed in liver metastases from breast, colon, and NSCLC, suggesting a conserved mechanism across epithelial cancers.
Conclusions
The liver microenvironment actively promotes metastatic competency by inducing a HIF1alpha-ACLY-acetyl-CoA-driven stem-like state in disseminated tumor cells. ACLY inhibition disrupts this metabolic-epigenetic reprogramming and markedly suppresses liver metastatic outgrowth, highlighting ACLY as a tractable therapeutic target for liver metastasis.
利益披露 Disclosure
A. K. Sharma, None..
N. Takahashi, None..
C. Schultz, None..
Y. Huang, None..
S. Neel, None..
C. Febres Aldana, None.