FUS失活通过上调CD36促进肺癌的软脑膜转移
FUS inactivation promotes leptomeningeal metastasis of lung cancer through the up-regulation of CD36.
作者
作者单位
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, China.
- China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
- Guangzhou National Laboratory, Guangzhou International Bio Island, 510005 Guangzhou, China.
- Department of Hematology, First Affiliated Hospital, Jinan University, 510632 Guangzhou, China.
- BioSyngen Pte Ltd., Singapore 536671, Singapore.
摘要
中文
非小细胞肺癌（NSCLC）伴软脑膜转移（LM）的预后极差。LM进展的调节因子仍不明确，阻碍了有效的临床干预。在此，我们进行了体内全基因组CRISPR筛选，发现FUS（fused in sarcoma）消融在PC9和A549细胞中均促进LM。FUS通过直接与PPARA（过氧化物酶体增殖物激活受体α）mRNA相互作用并使其不稳定来抑制CD36表达。CD36增强NSCLC细胞的脂肪酸摄取和氧化磷酸化。基质金属蛋白酶2（MMP2）通过CD36介导的脂肪酸代谢上调，使NSCLC细胞破坏内皮屏障。FUS缺陷的NSCLC细胞增加了神经内分泌分化（NED）相关标志物的表达，包括SOX2、MAP2、NSE和突触素（SYP）。它们还表现出神经元样突起，并以CD36依赖性方式在补充脑脊液的培养基中扩增。机制上，脂肪酸摄取增加乙酰辅酶A和H3K27ac修饰，促进NSCLC细胞中NED标志基因和MMP2的表达。在NSCLC细胞中，遗传或药理学抑制CD36或抑制NED相关标志物可阻碍LM并延长小鼠生存期。在NSCLC患者中，FUS下调或CD36或SYP上调与LM进展相关。因此，CD36介导的脂肪酸代谢和NED标志物对于NSCLC进展为LM至关重要，突出了CD36作为限制LM进展的有前景的治疗靶点。
English
The prognosis of non-small cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is dismal. The regulators of LM progression remain elusive, thus impeding effective clinical intervention. Here, we performed in vivo genome-wide CRISPR-based screens and found that fused in sarcoma (FUS) ablation promoted LM in both PC9 and A549 cells. FUS repressed CD36 expression by directly interacting with and destabilizing PPARA (peroxisome proliferator-activated receptor α) messenger RNA. CD36 augmented fatty acid uptake and oxidative phosphorylation in NSCLC cells. Matrix metallopeptidase 2 (MMP2) was up-regulated through CD36-mediated fatty acid metabolism, which enabled NSCLC cells to disrupt the endothelial barrier. FUS-deficient NSCLC cells increased the expression of neuroendocrine differentiation (NED)-related markers, including SRY-box transcription factor 2 (SOX2), microtubule-associated protein 2 (MAP2), enolase 2 (NSE), and synaptophysin (SYP). They also exhibited neurite-like extensions and expanded in cerebrospinal fluid-supplemented medium in a CD36-dependent manner. Mechanistically, fatty acid uptake increased acetyl-coenzyme A and H3K27ac modifications to promote the expression of NED signature genes and MMP2 in NSCLC cells. Genetic or pharmacological inhibition of CD36 or inhibition of NED-related markers in NSCLC cells hindered LM and prolonged survival in mice. In patients with NSCLC, down-regulation of FUS or up-regulation of CD36 or SYP was associated with progression to LM. Thus, CD36-mediated fatty acid metabolism and NED signature are crucial for progression to LM in NSCLC, highlighting CD36 as a promising therapeutic target to limit the progression of LM.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 15.6
- 新锐分区
- 1区