LBPO.TB02 · 肿瘤生物学 · Late-Breaking
FUS缺失通过上调CD36表达诱导神经内分泌分化样表型并促进肺癌软脑膜转移
FUS ablation induces neuroendocrine-differentiation-like phenotypes and promotes leptomeningeal metastases in lung cancer through upregulating CD36 expression
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
伴软脑膜转移（LM）的非小细胞肺癌（NSCLC）由于预后不良且缺乏明确的分子调控因子，仍是一项严峻的临床挑战。为填补这一空白，我们开展了体内全基因组CRISPR筛选以鉴定LM进展的关键驱动因子。我们发现FUS（Fused in sarcoma）的基因缺失在PC9和A549 NSCLC细胞系中均显著促进LM。在机制上，FUS通过直接相互作用并使PPARA mRNA不稳定，从而抑制CD36的表达。FUS的缺失导致CD36水平升高，进而增强NSCLC细胞的脂肪酸摄取和氧化磷酸化（OXPHOS）。这种由CD36介导的代谢重编程上调基质金属蛋白酶2（MMP2），使肿瘤细胞得以突破内皮屏障。FUS缺陷的NSCLC细胞还表现出神经内分泌分化（NED）样特征，其特点为NED标志物（如SOX2、MAP2、NSE、SYP）表达增加、神经突样延伸，以及在补充脑脊液（CSF）的培养条件下以CD36依赖方式的强劲增殖。使用抑制剂SSO靶向CD36可减少脂肪酸摄取、抑制NED特征基因表达，并抑制CSF环境中的肿瘤扩增。机制分析显示，脂肪酸代谢增加了乙酰辅酶A（acetyl-CoA）的可利用性和H3K27ac组蛋白修饰，从而促进NSCLC细胞中NED特征基因和MMP2的表达。在临床前模型中，对CD36进行基因或药理学抑制，或抑制NSCLC细胞中的NED特征，均阻碍了LM并延长了小鼠的生存期。在NSCLC患者中，FUS下调和CD36或SYP上调与侵袭性LM进展相关。此外，CD36表达在疾病进展和治疗过程中动态波动，凸显了其作为监测治疗反应生物标志物的潜力。总之，CD36介导的脂肪酸代谢和NED特征对NSCLC中的LM进展至关重要，凸显了CD36作为潜在LM生物标志物和LM治疗有前景的治疗靶点。
查看英文原文 English abstract
Non-small cell lung cancer (NSCLC) with leptomeningeal metastases (LM) remains a devastating clinical challenge due to its poor prognosis and the lack of well-defined molecular regulators. To address this gap, we performed in vivo genome-wide CRISPR-based screens to identify key drivers of LM progression. We discovered that genetic ablation of FUS (Fused in sarcoma) significantly promotes LM in both PC9 and A549 NSCLC cell lines. Mechanistically, FUS suppresses CD36 expression by directly interacting with and destabilizing PPARA mRNA. Loss of FUS leads to elevated CD36 levels, which in turn enhances fatty acid uptake and oxidative phosphorylation (OXPHOS) in NSCLC cells. This metabolic reprogramming, mediated by CD36, upregulates matrix metalloproteinase 2 (MMP2), enabling tumor cells to breach the endothelial barrier. FUS-deficient NSCLC cells further exhibit neuroendocrine differentiation (NED)-like features, characterized by increased expression of NED markers (e.g., SOX2, MAP2, NSE, SYP), neurite-like extensions, and robust proliferation in cerebrospinal fluid (CSF)-supplemented culture conditions in a CD36-dependent manner. Targeting CD36 with the inhibitor SSO reduces fatty acid uptake, suppresses NED signature gene expression, and inhibits tumor expansion in the CSF environment. Mechanistic analysis shows that fatty acid metabolism increases acetyl-CoA availability and H3K27ac histone modifications to promote the expression of NED signature genes and MMP2 in NSCLC cells. In preclinical models, genetic or pharmacological inhibition of CD36, or inhibition of NED signature in NSCLC cells hindered LM and prolonged survival in mice. In NSCLC patients, FUS downregulation and CD36 or SYP upregulation were associated with aggressive LM progression. Moreover, CD36 expression dynamically fluctuates during disease progression and treatment, highlighting its potential as a biomarker for monitoring therapeutic responses. Collectively, CD36-mediated fatty acid metabolism and NED signature are crucial for LM progression in NSCLC, underscoring CD36 as a potential LM biomarker and a promising therapeutic target for LM treatment.
利益披露 Disclosure
P. Li,
Guangdong Zhaotai Cell Bioscience Ltd. g., Board of Directors, non-salaried role), Patent.
Wellington Zhaotai Therapeutic Ltd. g., Board of Directors, non-salaried role).
S. Lin, None..
K. Yin, None..
M. Zheng, None..
H. Tu, None..
Y. Li, None..
Y. Wu, None.